Method of manufacturing pharmaceutical compositions

ABSTRACT

The present invention relates to pharmaceutical composition, comprising certain phosphate binder particles having a certain particle size distribution, a process for the manufacture of the pharmaceutical composition and the use of sucroferric oxyhydroxide having a certain particle size distribution for the manufacture of a pharmaceutical composition.

BACKGROUND OF THE INVENTION

This invention relates to a pharmaceutical composition comprising acertain phosphate binder, said phosphate binder comprises particleshaving a certain particle size distribution particularly adapted for thepreparation of improved tablets and other pharmaceutical compositions.

WO 20101015827 A2 discloses a ferric iron composition for use in amethod of treating hyperphosphatemia, wherein the ferric ironcomposition is a solid ligand-modified poly oxo-hydroxy metal ionmaterial represented by the formula (MxLy(OH)n), wherein M one or moremetal ions that comprise Fe3+ ions, L represents one or more ligandsthat comprise a carboxylic acid ligand, or an ionised form thereof, andOH represents oxo or hydroxy groups and wherein the material has apolymeric structure in which the ligands L are substantially randomlysubstituted for the oxo or hydroxy groups and wherein the solidligand-modified poly oxo-hydroxy metal ion material having one or morereproducible physico-chemical properties. While this document mentionscertain particle sizes of the solid ligand-modified poly oxo-hydroxymetal ion material, it does not disclose any particle size distributionfor a particular pharmaceutical composition, but only a particle sizedistribution of the freshly prepared phosphate binder materials.Accordingly this document does not teach anything about the relevance ofthe particle size distribution to be used for a pharmaceuticalcomposition. WO 20101015827 A2 does not contain any example of aspecific pharmaceutical composition.

U.S. Pat. No. 5,514,281 relates to a process for the selective reductionof the amount of inorganic phosphate in an aqueous liquid feedcontaining protein, in addition to said inorganic phosphate, withoutsignificantly adversely affecting said protein, which comprises:contacting an aqueous liquid feed, containing phosphate ions andprotein, with an adsorbent composition comprising; at least onepolynuclear metal oxyhydroxide covalently bound to an adsorbent basematerial. It mentions some particle sizes of the adsorbent base orsupport material (e.g. silicate, silicon dioxide, glyceryl modifiedsilicagel, a glyceryl modified glass, and a polymer), but not for thephosphate adsorbent and the polynuclear metal oxyhydroxide. In theexamples the phosphate binder is used in an extracorporeal treatment.There is no disclosure of a specific administrable pharmaceuticalcomposition except for known soluble metal oxyhydroxide/polyolcomplexes.

SUMMARY OF THE INVENTION

This invention relates further to certain pharmaceutical compositions,especially to chewable tablets, tablets, mini-tablets (micro-tablets)formed with and without prior processing like wet granulation or drygranulation (e.g roller compaction), granulate and tablets especiallyformed by direct compression of a certain phosphate binder compound(hereinafter phosphate binder), a process for the preparation thereof,new powders comprising the phosphate binders capable of being directlycompressed into tablets and or filled into capsules or sachets or othersuitable carrier systems (e.g. dispenser for mini tablets). Theinvention further relates to a process for preparing the pharmaceuticaladministration form, e.g. by blending the active ingredient and specificexcipients into the new formulations and then compressing or directlycompressing the formulations into the final form (e.g. direct compressedtablets) or the filling and use in e.g. dispensers or sachets.

The phosphate binders according to the present invention include inparticular “iron oxy-hydroxide based stabilized by a stabilizationagent” or “stabilized iron oxy-hydroxide phosphate binders” as describedin WO9722266 A1 and WO2009062993 A1. The wording “iron oxy-hydroxide,which is stabilized by a stabilization agent” or “stabilized ironoxy-hydroxide phosphate binders”, includes preferably an ironoxy-hydroxide together with a stabilization agent, which includes inparticular carbohydrates and humic acid. As described in WO9722266 A1such stabilization agent is suitably not bound as a complex compound tothe iron oxy-hydroxide, which means for example that a water-solublestabilization agent can be removed by washing the stabilized ironoxy-hydroxide with water. As further described in EP WO9722266A1 thestabilization agent is supposed to stabilize the iron oxy-hydroxidestructure, and to prevent ageing of the iron oxy-hydroxide, therebysecuring and preserving its phosphate adsorption capacity. This meansthat a stabilized iron oxy-hydroxide (FeOOH) in general has a higherphosphate adsorption capacity (as measured in EP WO9722266 A1) comparedto a non-stabilized iron oxy-hydroxide. In accordance with the presentinvention a preferred “iron oxy-hydroxide, which is stabilized by astabilization agent” comprises beta iron oxy-hydroxide stabilized asdescribed in WO9722266A1 with at least one carbohydrate and/or humicacid. In accordance with the present invention the iron moiety containspreferably a hydrated polynuclear oxy-hydroxide array “wrapped” by notcovalently bond carbohydrates, in particular, sucrose as sugar. Thepresence of the carbohydrates, in particular, sucrose as sugar issupposed to be essential for the maintenance of the hydrated structureof the polynuclear oxy-hydroxide and therefore for the high phosphatebinding capacity. Sucrose and starches are the carbohydrates that arepreferably used. The sucrose is supposed to prevent dehydration(“ageing”) of the polynuclear iron(III)-oxyhydroxide, and the starchesare supposed to improve processability during production. The ironoxy-hydroxide (FeOOH) can be in the form of microcrystals, such as inthe form of β-FeOOH. The repeating moiety of the iron-oxyhydroxidemicrocrystals can be described by the molecular formula FeOOH. Thepreferred β-FeOOH structure (akaganeite) contains anions arranged in abody-centered cubic array with Fe(III) ions occurring on the octahedralsites. The structure consists of double chains of edge-shared octahedralrunning parallel to the fourfold symmetrical b-axis.

Generally, due to their chemical nature the iron oxy-hydroxides used andadministered in accordance with the present invention essentially arenot absorbed by the human body.

The term “stabilization agent” as used herein includes preferably atleast one carbohydrate and/or humic acid, in particular, as described inWO9722266A1. In one embodiment at least one carbohydrate is soluble inwater. Carbohydrates include at least one mono-, di- or polysaccharide,such as agarose, dextran, dextrin, dextran derivatives, cellulose andcellulose derivatives, saccharose (sucrose), maltose or lactosepreferably saccharose (sucrose), dextrin or starch.

The term “starch” as used herein includes any conventionally used starchproducts (such as potato starch, corn starch, rice starch, tapiocastarch) in native, pregelatinized, degraded, modified, and derivatizedforms, preferably suitable for direct compression, and mixtures thereof.Most preferred products include native and pregelatinized starch, suchas in a mixture having a ratio (native-pregelatinized) in theweight-range of 10:1 to 0.5:1, preferably in the range of 3:1 to 0.5:1more preferably in the range of 2:1 to 1:1.

Preferably the phosphate binder is sucroferric oxyhydroxide (USAN name)or defined by the WHO under the ATC code as V03AE05, or also known asPA21, which is a mixture of iron(III) oxyhydroxide, sucrose, starches.

The preferred phosphate binder comprises polynucleariron(III)-oxyhydroxide stabilized by sucrose, and starches (known assucroferric oxyhydroxide or PA21 (PA21-1 or PA21-2)) or a polynuclearβ-iron(III)-oxyhydroxide stabilized by sucrose, and starches (known assucroferric oxyhydroxide or PA21 (PA21-1 or PA21-2)). A particularlypreferred mixture of iron(III) oxyhydroxide, sucrose and starchescomprises about 25 to 40 wt-% iron(III) oxyhydroxide, about 25 to 40wt-% sucrose and about 25 to 40 wt-% starches based on the total dryweight (i.e. 100 wt-%) of phosphate binder particles based on suchmixture. A particular preferred mixture of iron(III) oxyhydroxide,sucrose and starches comprises about 30 to 35 wt-% iron(III)oxyhydroxide, about 30 to 35 wt-% sucrose and about 30 to 35 wt-%starches based on the total dry weight (i.e. 100 wt-%) of phosphatebinder particles based on such mixture, wherein the iron(III)oxyhydroxide preferably comprises β-iron(III) oxyhydroxide.

In the present invention the term “sucroferric oxyhydroxide” covers amixture of iron(III) oxyhydroxide, sucrose and starches, wherein themixture comprises one, two or more starches e.g. only native starch(PA21-1) or only pregelatinized starch or a mixture of native starch andpregelatinized starch (PA21-2), etc. A preferred “sucroferricoxyhydroxide” contains a mixture of native starch and pregelatinizedstarch as herein above defined.

In each case in particular in the claims and the final products of theworking examples, the subject matter of the final products, thepharmaceutical preparations and the claims are hereby incorporated intothe present application by reference to the herein mentionedpublications or patent applications.

As is known to the skilled person in the art “phosphate binders” arecompounds or compositions that are capable to act as an adsorbent forphosphate from aqueous medium, for example from aqueous solutions, inparticular from physiological aqueous solutions. They are particularlysuitable as an adsorbent for inorganic phosphate and phosphate bonded tofoodstuffs, especially in a preparation for oral application for theprophylaxis and treatment of hyperphosphataemia conditions, inparticular in patients with chronic renal insufficiency, which have apathologically increased serum phosphate level due to the decrease inthe glomular filtration rate. The term “phosphate binders” according tothe present invention covers any salt, isomer, enantiomer or crystalform of such active ingredient.

The phosphate binders, e.g. sucroferric oxyhydroxide, may be combinedwith one or more pharmaceutically acceptable carriers and, optionally,one or more other conventional pharmaceutical adjuvants and administeredenterally, e.g. orally, in the form of tablets, chewable tablets,mini-tablets (micro-tablets), granules, capsules, caplets, granules,powders etc. The enteral compositions may be prepared by conventionalmeans or enabling technologies.

The phosphate binders e.g. sucroferric oxyhydroxide, may be formulatedinto pharmaceutical compositions containing an amount of the activesubstance (phosphate binders) that is effective for treatinghyperphosphatemia or conditions resulting from unbalanced phosphatelevels (e.g. for therapeutic use in the control of serum phosphorouslevels in patients with Chronic Kidney Diseases (CKD) who are ondialysis), such compositions comprising a pharmaceutically acceptablecarrier, and such compositions being formulated into unit dosage formsor multiple dosage preparations.

In view of their ability to adsorbs the dietary phosphate in thegastrointestinal tract, the phosphate binders, are useful in treatingunbalanced phosphate levels and conditions resulting from unbalancedphosphate levels (e.g. for therapeutic use in the control of serumphosphorous levels in patients with CKD who are on dialysis, ortreatment of hyperphosphatemia).

The phosphate binders especially sucroferric oxyhydroxide, useful inthis invention should preferably not be mixed with humid/wet excipients,and are not inherently compressible. Consequently, there is a need toprovide a free-flowing and cohesive pharmaceutical formulations in theform of a powder or granulate, used as such e.g. filled into capsules orsachets or dispensing units, with or without dosing aid, compressed ordirectly compressed into tablets, chewable tablets, mini-tablets(micro-tablets) or comparable dosage forms.

Tablets may be defined as solid dosage pharmaceutical forms containingone or more drug substances with or without suitable inert materialsknown as excipients. They are produced by compression of apharmaceutical formulation, in the form of a powder or granules orsmaller dosing units (e.g. mini-tablets, pellets), containing thephosphate binder and certain excipients. Without excipients most drugsand pharmaceutical ingredients cannot be directly-compressed intotablets. This is primarily due to the poor flow and cohesive propertiesof most drugs.

There has been widespread use of tablets and the majority ofpharmaceutical dosage forms are marketed as tablets. Major reasons fortablet and chewable tablet popularity as a dosage form are simplicity ofuse, low cost and the speed of production. Other reasons includestability of drug product, convenience in packaging, shipping anddispensing. To the patient or consumer, tablets offer convenience ofadministration, ease of accurate dosage, compactness, portability,blandness of taste, and ease of administration.

Tablets may be plain, film or sugar coated bisected, embossed, layeredor sustained-release. They can be made in a variety of sizes, shapes andcolors. Tablets may be swallowed, chewed or dissolved in the buccalcavity or beneath the tongue. They may be dissolved in water for localor topical application.

Other desirable characteristics of excipients and active ingredientsinclude the following:

-   -   High-compressibility to result strong tablets at low compression        forces;    -   Narrow particle size distribution;    -   Good flow properties that can improve the flow of other        components in the formula; and    -   Cohesiveness (to prevent tablet from crumbling during        processing, shipping and handling).

There are four commercially important processes for making compressedtablets: wet granulation followed by compression, direct compression,dry granulation (slugging or roller compaction) followed by compressionand extrusion (e.g. melt extrusion) followed by compression. The methodof preparation and the type of excipients used are tailored to give thetablet formulation the desired physical characteristics that allow forthe rapid compression of the tablets. After compression, the tabletsmust fulfill a number of attributes, such as e.g. appearance, hardness,disintegration time, friability, uniformity of mass, chewability, anddissolution profile. Choice of fillers and other excipients will dependon the chemical and physical properties of the drug, behavior of themixture during processing and the properties of the final tablets.

The properties of the drug, its dosage forms and the economics of theoperation will determine selection of the best process for tableting.

The dry granulation method may be used where one of the constituents,either the drug or an excipient, and/or the mixture thereof hassufficient cohesive properties to be compacted. The method consists ofblending, slugging the ingredients, compaction, dry screening,lubrication and compression.

The wet granulation method is used to convert a powder mixture intogranules having suitable flow and cohesive properties for tableting. Theprocedure consists of mixing the powders in a high-shear granulatorfollowed by adding the granulating solution under shear to the mixedpowders to obtain a granulation or to add the liquid by spraying in afluid bed dryer to result the granulate. The damp mass may be screenedthrough a suitable screen and dried by tray drying or other suiteddrying techniques. The overall process may include weighing, dry powderblending, wet granulating, drying, milling, blending lubrication andcompression.

Typically drug substance powders do not have sufficient adhesive orcohesive properties to form hard, strong granules. A binder is usuallyrequired to form larger particles (granules). Heat and moisturesensitive drugs mostly cannot be manufactured using wet granulation. Thedrawback of this the wet granulation technology is the number ofprocessing steps and needed processing time materializing in themanufacturing costs.

Direct compression is regarded as preferred process where the solidcomponents are compressed directly without changing the physicochemicalproperties of the drug. The active ingredient(s), direct compressionexcipients and other auxiliary substances, such as a glidant andlubricant are blended in a bin blender before being compressed intotablets. The advantages of the direct compression technology includee.g. the uniformity of the blend, few manufacturing steps involved,i.e., the overall process involves weighing of powders, blending andcompression, hence limited cost; eradication of heat and moisture, primeparticle dissociation and physical stability.

Pharmaceutical manufacturers do prefer to use direct compressiontechniques over wet or dry granulation methods because of the shortprocessing time and limited process steps resulting in advantageouscost. Direct compression however is usually limited to cases where theactive ingredient has acceptable physicochemical characteristicsrequired to form a pharmaceutically acceptable dosage form. Many activeingredients do no exhibit all necessary properties and therefore oftenmust be combined with suited excipients to allow for direct compression.Since each excipient added to the formulation increases the tablet sizeof the final product, manufacturers are often limited to using thedirect-compression method in formulations containing a low dose of theactive ingredient per compressed tablet.

A solid dosage form containing a high-dose drug, i.e. the drug itselfcomprises a substantial portion of the total compressed tablet weight,can only be directly compressed if the drug itself has appropriatephysical characteristics, e.g. cohesiveness, to be directly compressed.

The claimed pharmaceutical composition, comprising phosphate bindersespecially sucroferric oxyhydroxide is considered a high-dose drug i.e.high-dose of sucroferric oxyhydroxide per unit dosage form (e.g. pertablet). Unit dosage formulations can include above 60%, 70%, 80%, or90% and more by weight of the phosphate binder per unit dosage form(e.g. per tablet). A single oral dosage form of the phosphate bindersespecially sucroferric oxyhydroxide shall contain preferably more than400 mg, or more than 800 mg or more than 1000 mg or more than 1500 mg ormore than 2000 mg or 2500 mg of phosphate binder. This high-dose drug,combined with its rather poor physical characteristics for directcompression, has not permitted the use of the direct compressiontechnology to prepare the final product with acceptable physicalcharacteristics. The phosphate binders are relatively unstable in thepresence of free water (or have poor microbiological stability), afactor militating against the use of the wet granulation technology (thelarge amount of phosphate binder in an adequate single dose formulationwould require too much water).

Earlier used tablets comprising sucroferric oxyhydroxide, such asdescribed in the patent application WO2009/062993 did only partiallymeet the expected physical characteristics e.g. still remainingpotential cohesiveness issues. Tablets could more easily break, and hadstill not an acceptable friability or hardness or compressibility orchewability or disintegration time or dissolution profiles.

As patients suffering from unbalanced phosphate levels (e.g. patientswith CKD (Chronic Kidney Diseases) who are on dialysis) need to beadministered with several oral dosage forms per day, over several monthsor years, there is a clear need for improvement of the oral dosage formse.g. improved physical characteristics.

All % weights (w/w) throughout this description are expressed inrelation to the total weight of the pharmaceutical composition (drycomposition), if not indicated otherwise.

Another limitation of direct compression as a method of tabletmanufacturing is the potential size of the compressed tablets. Theamount of excipients needed in wet granulation is less than thatrequired for direct compression since the process of wet granulationcontributes toward the desired physical properties of the tablet.

Therefore, if the amount of active ingredient is high, a pharmaceuticalformulator may choose to wet granulate the active ingredient with otherexcipients to attain an acceptable sized tablet with the desired amountof active ingredient. As herein described, the phosphate bindersespecially sucroferric oxyhydroxide is preferably administered to thepatients as single dosage form, wherein said dosage form contains a highdrug load of phosphate binder. Furthermore, due to the behavior of theclaimed phosphate binders in the presence of water, it is desirable toperform direct compression of tablets containing high-dose phosphatebinders especially sucroferric oxyhydroxide. Therefore, there is strongtechnical hurdles which need to be overcome in order to manufacturecompressed (or direct compressed) big sized tablets which exhibitacceptable friability, hardness, chewability, cohesiveness,disintegration time and dissolution profiles.

Depending on the intended use of the tablet, i.e. whether it is forintact swallowing or rapid disintegration (in the oral cavity or in asmall amount of liquid prior to ingestion) or to be chewed, such as e.g.a chewable tablet, usually excipients, such as disintegrants,superdisintegrants, glidants, lubricants, binder compression aids andthe like may be added if desired. The tablet may be coated or not, aspharmaceutically necessary or desired.

Thus, the pharmaceutical composition of the invention includes anydosage form suitable for oral administration and in particular mayinclude tablets (preferably direct compressed tablets and pills, eitherin a form for intact swallowing (e.g. also film-coated) or in a formcapable of rapid disintegration (either in the oral cavity afteringestion or in a small amount of liquid prior to ingestion), includingchewable forms, mini tablets, dry powders, granules, capsules or sachetscontaining these granules or mini-tablets (micro-tablets), wafers,lozenges, and the like. The form for intact swallowing may befilm-coated, if desired. The pharmaceutical composition of the inventionincludes also powders or granules which can be compressed or compactedinto tablets.

Preferred dosage forms include tablets and pills, either in a form forintact swallowing (e.g. film-coated) in or in a chewable form, granulesand capsules or sachets containing these granules, and lozenges. In thecase of orally administrate dosage forms, if desired film-coated, theseare swallowed intact and disintegration takes place in the stomachor/and other parts of the intestine, whereupon the active agent isreleased for adsorption of phosphate to reduce its systemic uptake.

With the herein claimed pharmaceutical formulations, compositions, andtablets, the administration can be at as minimal as 3 to 4 unit dosageforms per day.

As herein described, the phosphate binders especially sucroferricoxyhydroxide is preferably administered to the patients in the form of asingle dosage form per administration, wherein said dosage form containsa high load of phosphate binder i.e. more than 400 mg or more than 800mg or more than 1000 mg or more than 2000 or more than 2500 mg ofphosphate binders, preferably between 1500 to 3000 mg or between 2000 to3000 mg of phosphate binders. Dependent on the API load, the choice ofappropriate solid dosage form is limited. The most common options toresult unit dosage forms with high drug substance content are:powder/granulate/minitablet filled sachets, effervescent tablets orchewable tablets. Chewable tablets offer the advantage of moreflexibility in not requiring access to water and in the fact that themedication can be more discretely taken, i.e. at work, while travellingor at social occasions. In addition, avoiding additional water intake isof advantage for the patient group with CKD (Chronic Kidney diseases).Also, surveys indicate that patients prefer to take a single dose e.g. atablet per administration instead of multiple dose like it would berequired with swallowable tablets or tablet with smaller size for highdosed medications. The mechanical strength of chewable tablets canhowever be of concern with regard to damage to teeth or mandibularjoints from chewing tablets with unsuitable mechanical properties. AsCKD patients have to chew several tablets per day for several months oryears, the chewability of the tablets is critical. Several testingprocedures and additional methods with the objective of obtaining ameaningful evaluation of the chewability of tablets and confirming theappropriateness of the phosphate binder selected formulations/tabletsfrom the chewability perspective were applied.

In the present invention the “pharmaceutical compositions” comprise thephosphate binder compound as active ingredient (preferably one, two orthree) and preferably at least one pharmaceutically acceptableexcipient, which can be in the form of a powder (to be incorporated intosachet or capsules, preferably a dry powder), of tablets (compressedinto tablets, preferably mono, bi or tri layer tablet), pills, granulesor micro granules, capsules, pellets, wafers, lozenges or coated tablet.

In the present invention, the term “granules” do also covermicro-granules. The granules can be used for direct administration orfurther processed into tablets, mini-tablets, chewable tablets.

In the present invention, the term “tablet” covers any type of tabletresulting from the compression or compaction of powders, granules(obtained by wet or dry granulation, tableting, melt extrusion),mini-tablets, micro granules, pellets, but refers preferably a directcompressed tablet.

In the present invention the term “compressed” covers any physicalcompaction process resulting in solid dosage units.

In the present invention, the term “pharmaceutical formulations (orformulations)” covers mixture of active ingredients (preferably one, twoor three) and pharmaceutically acceptable excipients, which are in aform adapted to the preparation/manufacturing of a pharmaceuticalproduct (e.g. pharmaceutical composition). In the present invention thepreferred formulations are powders or granules adapted for compaction orcompression or direct compression into tablets.

It is also an object of the invention to provide phosphate binders ashereinafter described, in the form of a pharmaceutical formulation,preferably in the form of a free-flowing, cohesive tableting powder(powder formulation), capable of being compressed or directly compressedinto a tablet.

It is also an object of the invention to provide a phosphate binder ashereinafter described, in the form of a pharmaceutical formulation,preferably in the form of tableting granules (obtained by wet or drygranulation or melt extrusion) which can be mixed with furtherexcipients, capable of being compacted, compressed or directlycompressed into a tablet.

It is a further object of the invention to provide a compressed (ordirectly compressed) phosphate binder tablet in unit dosage form havingan acceptable dissolution profile, as well as acceptable degrees ofhardness and resistance to chipping, as well as acceptable friabilityand chewability profiles, as well as a fast disintegration time.

It is a further object of the invention to provide a compressed (orpreferably direct compressed) phosphate binder tablet which is a rapiddisintegration tablet (in the oral cavity or in a small amount of liquidprior to ingestion), like e.g. a chewable tablet or mini tablets.

It is a further object of the invention to provide a process forpreparing a compressed phosphate binder tablet by direct compression ina unit dosage forms.

The present invention also provides a tableting, free-flowingparticulate phosphate binder composition in the form of a tabletingpowder (comprising preferably at least one additional pharmaceuticallyacceptable excipient as herein after described), capable of beingcompressed, or directly compressed into a tablet having adequatehardness, friability, chewability, rapid disintegration time and anacceptable dissolution pattern.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be described in greater detail with referenceto the accompanying drawings in which

FIG. 1 schematically illustrates a flowchart for manufacturing thephosphate binder particles according to the present invention,

FIG. 2 illustrates a graph of particle size distribution analyzed in thephosphate binder particles according to the present invention,

FIG. 3 illustrates a graph of hardness of the phosphate binder particlesaccording to the preset invention, and

FIG. 4 illustrates a graph of compression force of a tablet includingthe phosphate binder particles according to the present invention.

DETAILED DESCRIPTION

In the development of the herein described pharmaceutical compositionsthe applicant has discovered that it is particularly advantageous to usea pharmaceutical composition, especially in the form of a tablet,preferably a compressed tablet, comprising a phosphate binder, saidphosphate binder comprises particles having a particle sizedistribution, wherein at least 40% of the particles have a particle sizewithin the range of 4 to 200 μm.

Preferably:

-   -   i) the particles of the phosphate binder especially of        sucroferric oxyhydroxide, have a particle size distribution with        particles in the range of 4 to 200 μm, preferably wherein at        least 40% (by volume) of the particles have a particle size in        the range of 4 to 200 μm, and/or    -   ii) the phosphate binder particles especially the sucroferric        oxyhydroxide particles have a d50 in the particle size        distribution which is in the range of 30 μm to 120 μm, or 35 μm        to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably        of 40 μm to 80 μm, or 42 μm to 75 μm, and/or    -   iii) the hardness of the tablets is between 70 to 250 N or 85 to        250 N or 85 to 200N or 70 to 200 N or 80 to 200 N, and/or    -   iv) the tablet friability is between 0% to 7% or between 0.05%        to 7%, and/or v) the tablet has a disintegration time of less        than 30 min, preferably between 5 and 20 min, and/or    -   vi) the tablet diameter is between 15 mm to 30 mm, the tablet        weight is between 2000 mg to 3000 mg and the tablet thickness is        between 4.5 mm and 7.5 mm.

In particular, the present invention concerns a pharmaceuticalcomposition or a compressed pharmaceutical tablet preferably a directcompressed tablet, comprising a phosphate binder. Said phosphate binder,especially sucroferric oxyhydroxide, has unfavorable physical propertiesto be converted into an acceptable compressed preferably directcompressed pharmaceutical tablet. These unfavorable physical propertiescan be e.g. bulkiness, sticking, fluffiness and the like. Duringdevelopment of the herein described pharmaceutical compositions andtablets, the applicant has discovered that the processing properties orphysical properties of the pharmaceutical formulation, such ashygroscopicity, flowability, bulkiness, fluffiness is unexpectedlyimproved if the particles comprising the phosphate binder especiallysucroferric oxyhydroxide have a particle size distribution wherein atleast 40%, or at least 60%, or at least 80%, or at least 90% by volumeis in the range of 4 to 200 μm (preferably in the range of 5 to 160 μm)and/or a d50 (related to the volume of the particles) in the particlesize distribution in the range of 30 μm to 120 μm or 35 μm to 110 μm or40 μm to 108 μm or 40 μm to 100 μm, or preferably of 40 μm to 80 μm(preferably in the range of 42 μm to 75 μm). The applicant alsosurprisingly discovered that the tablets show improved physicalcharacteristics such as solubility, friability, hygroscopicity,hardness, compressibility, chewability, or disintegration.

An additional unexpected advantage of the selected particle sizedistribution, is the possibility to increase the compression forceduring the tableting process, without any alterations (except hardness)of the tablet physical properties but with the possibility to increasethe tablet hardness to the targeted hardness range.

In a preferred first embodiment (a) the present invention concernscompressed tablets preferably direct compressed pharmaceutical tablets,wherein the powder to be compressed contains particles comprising aphosphate binder (the phosphate binder particles) especially sucroferricoxyhydroxide, and at least one further pharmaceutically acceptableexcipient, and wherein at least 40%, preferably 60%, most preferably 80%even more preferably 90% (by volume) of the particles of the phosphatebinder particle size distribution in the tablet are between 4 to 200 μmor between 5 to 160 μm or between 21 to 160 μm.

In a preferred second embodiment (b) the present invention concernscompressed tablets preferably direct compressed pharmaceutical tablets,wherein the powder to be compressed contains particles comprising aphosphate binder (the phosphate binder particles) especially sucroferricoxyhydroxide, and at least one further pharmaceutically acceptableexcipient, and wherein the phosphate binder particles have a d50 (byvolume) in the particle size distribution in the range of 30 μm to 120μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, orpreferably of 40 μm to 80 μm or preferably in the range of 42 μm to 75μm.

In a preferred third embodiment (c) the present invention concernscompressed tablets preferably direct compressed pharmaceutical tablets,wherein the dispersion contains particles comprising a phosphate binder(the phosphate binder particles) especially sucroferric oxyhydroxide andat least one further pharmaceutically acceptable excipient, and wherein:

-   -   i) at least 40%, preferably 60%, most preferably 80% even more        preferably 90% (by volume) of the particles in the phosphate        binder particle size distribution are between 4 to 200 μm or        between 5 to 160 μm or between 21 to 160 μm, and    -   ii) the phosphate binder particles have a d50 (by volume) in the        particle size distribution between 30 μm to 120 μm, or 35 μm to        110 μm, or 40 μm to 108 μm, or 40 μm to 100 μm, or preferably of        40 μm to 80 μm or preferably between 42 μm to 75 μm, and/or    -   iii) the hardness of the tablets is between 70 to 250 N, and/or    -   iv) the tablets friability is between 0% to 7% or 0.05% to 7%,        and/or    -   v) the tablet has a disintegration time of less than 30 min,        preferably between 5 and 20 min, and/or    -   vi) the tablet diameter is between 16 mm to 30 mm, the tablet        weight is between 1500 mg to 3000 mg (preferably 2000 to 3000        mg) and the tablet thickness is between 4.5 mm and 7.5 mm,        and/or,    -   vii) the tablet contains between 1500 mg to 3000 mg of phosphate        binder especially sucroferric oxyhydroxide.

In a preferred fourth embodiment (d) the present invention concerns apharmaceutical composition, which contains particles comprising aphosphate binder especially sucroferric oxyhydroxide and at least onefurther pharmaceutically acceptable excipient, and wherein the phosphatebinder particles have a d50 in the particle size distribution between 30μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 108 μm, or 40 μm to 100μm, or preferably of between 40 μm to 80 μm or between 42 μm to 75 μm,wherein d50 relates to the volume of the particles.

In a preferred fifth embodiment (e) the present invention concerns apharmaceutical composition, which contains particles comprising aphosphate binder especially sucroferric oxyhydroxide and at least onefurther pharmaceutically acceptable excipient, and wherein at least 40%,preferably at least 60%, or preferably at least 80%, or at least 90% (byvolume) of the particle size distribution in the formulation orcomposition is between 4 to 200 μm or between 5 to 160 μm or between 21to 160 μm.

The term “wherein at least 40%, preferably at least 60%, or at least80%, or at least 90%” means that at least 40%, preferably at least 60%,or at least 80%, or at least 90% of the particles (phosphate binderparticles) are of the said size i.e. belong to the said size range. Thepercentages are volume-%.

The term “d50 particle size distribution” means that 50% (per volume) ofthe particles have a particle size above or below the defined d50 valueexpressed in μm.

The term “d10 particle size distribution” means that 10% (per volume) ofthe particles have a particle size lower than the d10 value expressed inμm.

The term “d90 particle size distribution” means that 90% (per volume) ofthe particles have a particle size lower than the d90 value expressed inμm.

These d-values relate in particular to the cumulative particle volume inthe particle distribution curve.

The combination of the above third embodiment (c) parameters providecompressed tablets preferably direct compressed tablets withparticularly improved physical characteristics as herein above defined.

Thus this invention concerns also compressed tablets (e.g. a chewabletablet), preferably direct compressed tablets, which contains particlescomprising a phosphate binder (the phosphate binder particles)especially sucroferric oxyhydroxide and at least one furtherpharmaceutically acceptable excipient and wherein one or more of thefollowing features i) to vii) is met:

-   -   i) at least 40%, preferably at least 60%, or preferably at least        80%, or at least 90% (by volume) of the particles of the        phosphate binder particle size distribution in the tablet are        between 4 to 200 μm or between 5 to 160 μm or between 21 to 160        μm,    -   ii) the phosphate binder particles have a d50 (especially by        volume) in the particle size distribution between 30 μm to 120        μm, or 35 μm to 110 μm, or 40 μm to 100 μm, or preferably of        between 40 μm to 80 μm or between 42 μm to 75 μm,    -   iii) the hardness of the tablets is between 70 to 250 N,    -   iv) the tablets friability is between 0% to 7% or between 0.05%        to 7%,    -   v) the tablets have a disintegration time of less than 30 min,        preferably between 5 and 20 min,    -   vi) the tablet diameter is between 16 mm to 30 mm and the tablet        weight is between 2000 mg to 3000 mg and the tablet thickness is        between 4.5 mm and 7.5 mm,    -   vii) the tablet contains between 1500 mg to 3000 mg of phosphate        binder especially sucroferric oxyhydroxide.

In a further embodiment, this invention concerns any of the hereindescribed compressed tablets, wherein the hardness of the tablets isbetween 85 to 250 N or between 70 and 200 N or 85 to 200 N, or between85 to 200 N or between 80 to 200 N or between 100 N to 230 N.

In a preferred embodiment, this invention concerns any of the hereindescribed compressed tablets preferably direct compressed pharmaceuticaltablets, preferably chewable tablets.

In a preferred embodiment, this invention concerns a chewable tablet ashereinabove described, wherein; i) the phosphate binder is sucroferricoxyhydroxide, and ii) the tablet contains between 1500 mg to 3500 mg orbetween 2000 to 3000 mg of sucroferric oxyhydroxide.

Preferably the phosphate binder particles in the formulation or tabletsespecially the sucroferric oxyhydroxide phosphate binder particles asherein described, represent more than 65% of the total tablet mass(total tablet weight), preferably more than 80% or more than 90% or evenmore than 95% of the total mass of the tablets (by weight on a dryweight basis) or of the formulation.

As described above the preferred phosphate binder to be used in thepharmaceutical compositions according to the invention comprisespolynuclear iron(III)-oxyhydroxide stabilized by sucrose, and starches(known as sucroferric oxyhydroxide or PA21) or a polynuclearβ-iron(III)-oxyhydroxide stabilized by sucrose, and starches (known assucroferric oxyhydroxide or PA21). Accordingly the particles ofsucroferric oxyhydroxide, i.e. consisting essentially of polynucleariron(III)-oxyhydroxide, sucrose, and starches have a particle sizedistribution wherein at least 40%, or at least 60%, or at least 80%, orat least 90% by volume is in the range of 4 to 200 μm (preferably in therange of 5 to 160 μm) and/or a d50 (related to the volume of theparticles) in the particle size distribution in the range of 30 μm to120 μm or 35 μm to 110 μm or 40 μm to 108 μm or 40 μm to 100 μm, orpreferably of 40 μm to 80 μm (preferably in the range of 42 μm to 75μm). A particularly preferred mixture of iron(III) oxyhydroxide, sucroseand starches comprises about 25 to 40 wt-% iron(III) oxyhydroxide, about25 to 40 wt-% sucrose and about 25 to 40 wt-% starches based on thetotal dry weight (i.e. 100 wt-%) of the phosphate binder particles ofsuch mixture. A particular preferred mixture of iron(III) oxyhydroxide,sucrose and starches comprises about 30 to 35 wt-% iron(III)oxyhydroxide, about 30 to 35 wt-% sucrose and about 30 to 35 wt-%starches based on the total dry weight (i.e. 100 wt-%) of phosphatebinder particles of such mixture, and the iron(III) oxyhydroxidepreferably comprises β-iron(III) oxyhydroxide.

Accordingly the sucroferric oxyhydroxide phosphate binder particles asherein described are the preferred active ingredient particles (i.e.particles of polynuclear iron(III)-oxyhydroxide stabilized by sucrose,and starches), before mixing such particles with other excipients.Preferably the sucroferric oxyhydroxide particles comprise more than 95%or even more than 98% of sucroferric oxyhydroxide, by weight on a dryweight basis of the particles (i.e. of the drug substance particlesbefore mixture with additional excipients). Preferably not more than 2%to 5% of side products or impurities resulting from manufacturingprocess should be present in the sucroferric oxyhydroxide particles(e.g. sodium chloride etc.). Active ingredient particles can also benamed drug substance (DS) particles.

Preferably the phosphate binder particles in the tablets orpharmaceutical compositions, especially the sucroferric oxyhydroxidephosphate binder particles as herein described, represent more than 65%,preferably more than 80%, or preferably more than 90% and even more than95% of the total weight of the tablet or of the pharmaceuticalcomposition (by weight on a dry weight basis).

Phosphate binder particles especially the sucroferric oxyhydroxideparticles can be formed by spray drying or an alternative sizeincreasing process well known in the field like e.g. granulation, directcompression etc. microgranulation.

Preferably the sucroferric oxyhydroxide particles comprise more than 65%of sucroferric oxyhydroxide, preferably more than 80% or preferably morethan 90% or even more than 95% or even more than 98% of sucroferricoxyhydroxide, by weight on a dry weight basis.

In a further embodiment the inventions relates to the herein describedtablets or pharmaceutical compositions, wherein the single oral dosageform of the phosphate binders especially sucroferric oxyhydroxide shallcontain preferably more than 400 mg, or more than 800 mg or more than1000 mg or more than 1500 mg or more than 2000 mg or more than 3000 mgof phosphate binder.

In a further embodiment the inventions relates to the herein describedtablets or pharmaceutical compositions, wherein the single oral dosageform of the phosphate binders especially sucroferric oxyhydroxide,contains between 800 mg to 3500 mg of sucroferric oxyhydroxide, orbetween 1500 mg to 3500 mg of sucroferric oxyhydroxide, or between 1500mg to 3000 mg of sucroferric oxyhydroxide, or between 2000 mg to 3000 mgof sucroferric oxyhydroxide.

The invention also relates to the herein described tablets orpharmaceutical compositions, wherein the phosphate binder particles havea d50 in the particle size distribution of between 40 μm to 80 μm andwherein at least 60%, most preferably at least 80% (by volume) of theparticles of the phosphate binder particle size distribution in thetablet is in between 4 to 200 μm or in between 5 to 160 μm or in between21 to 160 μm.

It has been discovered that the selected particle size distribution ofthe phosphate binder especially sucroferric oxyhydroxide areparticularly important to enable the compaction of the tablets ashereinabove described, among other advantages.

In a preferred embodiment, the phosphate binder according to the presentinvention is a polynuclear iron(III)-oxyhydroxide stabilized by sucrosebased phosphate binder including a polynuclear iron(III)-oxyhydroxidestabilized by sucrose and one or more starches, including naturalstarches (potato starch, corn starch etc.) and processed starches likepregelatinized starches.

In a further embodiment the present invention relates to apharmaceutical composition comprising sucroferric oxyhydroxide particlesand optionally at least one further pharmaceutically acceptableexcipient, wherein:

-   -   i) at least 40% or at least 60%, at least 80%, or at least 90%        (by volume) of the sucroferric oxyhydroxide particles in the        particle size distribution are between 4 to 200 μm or in between        5 to 160 μm or in between 21 to 160 μm,    -   ii) the sucroferric oxyhydroxide particles have a d50 (by        volume) in the particle size distribution of between 30 μm to        120 μm, or 35 μm to 110 μm, or 40 μm to 100 μm, or preferably of        between 40 μm to 80 μm,    -   iii) sucroferric oxyhydroxide as defined above represents more        than 80% or more than 90%, or more than 95%, or more than 97% of        the sucroferric oxyhydroxide particles, by weight on a dry        weight basis.

If there are further excipients in addition to the phosphate binderparticles the particle size distribution of the selected furtherexcipients comprised in the pharmaceutical formulation or apharmaceutical composition or tablets is similar to the particle sizedistribution of the phosphate binder particles preferably thesucroferric oxyhydroxide particles. The term “similar” means that theparticle size distribution of the excipients in the tablet comprisesparticles in the range of 5 to 400 μm, or between 5 to 300 μm,preferably between 1 to 200 μm. Preferably at least 40% or at least 60%,at least 80%, or at least 90% (by volume) of the excipient particles arein the range of 5 to 400 μm, or between 5 to 300 μm, preferably between1 to 200 μm.

The preferred excipients with an adapted particle size distribution canbe selected by use of e.g. the “Handbook of Pharmaceutical Excipients(6th edition), edited by Raymond C Rowe-Publisher: Science andPractice”.

Particle size of phosphate binders, e.g. sucroferric oxyhydroxideparticles size, can be controlled by crystallization, drying, preferablyspray drying, compaction and/or milling/sieving (non limiting examplesare described below). Producing the desired particle size distributionis well known and described in the art such as in “Pharmaceutical dosageforms: volume 2, 2nd edition, Ed.: H. A. Lieberman, L. Lachman, J. B.Schwartz (Chapter 3: SIZE REDUCTION)”. According to the presentinvention the desired particle size distribution in particular for thepreferably used sucroferric oxyhydroxide particles is obtained by aspray drying process, which comprises the step of spray-drying anaqueous suspension of the phosphate binder particles (being comprised ofa mixture of iron(III) oxyhydroxide, sucrose, starches in case of thepreferred sucroferric oxyhydroxide), wherein the aqueous suspension ofthe phosphate binder particles is subjected to atomization prior tospray-drying. Atomization of the feed might be generally achieved bybasic feed devices of the single fluid nozzle or pressure type, of thetwo-fluid nozzle or pneumatic type, and of the centrifugal (spinningdisc) type. In the present invention atomization is preferably done withthe centrifugal (spinning disc) type atomizer. Centrifugal atomizationachieves dispersion by centrifugal force, with the feed liquor beingpumped to a spinning disc. In the present invention in particular spraydrying on an Anhydro Spray drying plant type CSD No. 73 was found toresult in an appropriate drying process. For the atomization of theconcentrated aqueous PA21 suspension a centrifugal atomizer CE 250 canbe used, that atomizes by feeding the liquid feed onto a high-speedwheel. With a rotary atomizer, it is possible to adjust the wheel speedand thereby the particle size better than with a nozzle. Further, rotaryatomization is better suited for a shorter spray dryer. The powderreceived from the spray drying process should have a good flowabilityand the particle size of the dried product should not be too small. Withthe rotary atomizer, the particle size can be adjusted in particular byvariation of the wheel speed. The wheel speed of the atomizer definesthe size of the drops which fall into the drying chamber of the spraydryer. The size of the drops influences the particle size of the driedpowder as well as its loss on drying. A higher wheel speed producessmaller drops resulting in a smaller particle size of the dried powderand a lower loss on drying, because a smaller drop contains less waterwhich is faster vaporized during its way through the drying chamber.Since the correlation between the wheel speed and the particle sizedepends on the chamber geometry, it has to be adapted for eachindividual plant. For the geometry of the preferred Anhydro Spray dryingplant type CSD No. 73 used a wheel speed of between 12000 and 20000 rpm,was found to be suitable for achieving desired particle sizedistribution. The inlet temperature of the air defines the drying energywhich is brought into the spray dryer. Together with the inlet gas flowit defines the drying capacity. The inlet gas flow was kept constant atabout 1.9×10⁴ m³/h. The inlet temperature was found suitable in therange of 130-180° C. for the Anhydro Spray drying plant type CSD No. 73.

The desired particle size distribution in particular for the preferablyused sucroferric oxyhydroxide particles can be obtained from any form ofthe phosphate binder especially from any physicochemical form of thesucroferric oxyhydroxide (e.g. different secondary structures such asamorphous or crystalline forms).

Multiple particle sizes have been studied and it has been discoveredthat the herein described specific size range provides unexpected goodresults for compression, preferably direct compression and especiallyfor chewable tablets.

Particle size distributions might be measured using Sieve analysis, orlaser diffraction (international standard ISO 13320-1), or electronicsensing zone, light obstruction, sedimentation or microscopy which areprocedures well known by the person skilled in the art. Sieving is oneof the oldest methods of classifying powders by particle sizedistribution. A further method includes the determination of the volumeparticle size distribution by TEM (see e.g. Clariant Analytical ServicesTECHNICAL SHEET 106 TEM-Partikelgröße). Such methods are well known anddescribed in the art such as in any analytical chemistry text book or bythe United State Pharmacopeia's (USP) publication USP-NF (2004-Chapter786-(The United States Pharmacopeial Convention, Inc., Rockville, Md.))which describes the US Food and Drug Administration (FDA) enforceablestandards. The used techniques are e.g. described in Pharmaceuticaldosage forms: volume 2, 2nd edition, Ed.: H. A. Lieberman, L. Lachman,J. B. Schwartz is a good example. It also mentions (page 187) additionalmethods: Electronic sensing zone, light obstruction, air permeation,sedimentation in gas or liquid. However, the values of the particle sizedistributions used in the present invention are generally obtained bythe Laser diffraction analytical technologies (see for examplehttp://pharmazie-lehrbuch.de/kapitel/3-1.pdf). More specifically theparticle size distributions are obtained according to the invention witha LS 13 320 Laser Diffraction Particle Size Analyzer of Beckmann Coulterthereby relying in particular on the corresponding “LS 13 320 LaserDiffraction Particle Size Analyzer Instructions For Use PN B05577AB(October 2011)” using in particular the complete Mie theory. These laserdiffraction analytical technologies yield volume weighted distributions.Here the contribution of each particle in the distribution relates tothe volume of that particle (equivalent to mass if the density isuniform), i.e. the relative contribution will be proportional to size.More specifically the particle size distribution (PSD) in accordancewith the present invention is carried out with a 20 g sample of thephosphate binder which is analyzed with a laser particle size analyzerBeckman Coulter LS equipped with a dry powder system. A run length ofapprox 13″ and an obscuration of 4% is applied. The PSD is calculatedfrom the cumulative percentage undersize size distribution using acomputer program. Further details are shown in example 4 below.

Tablet thickness is measurable using a ruler, vernier caliper, a screwgauge or any electronic method to measure dimensions. Such methods arewell known and described in the art such as in any analytical chemistrytext book or by the United State Pharmacopeia's (USP) publication USP-NF(2004) which describes the US Food and Drug Administration (FDA)enforceable standards.

This invention provides in particular a compressed tablet or directcompressed tablet, especially chewable tablet, which is capable ofdisintegrating in water within a period of less than 30 minutes, orpreferably between 5 to 25 minutes to provide a dispersion which iscapable of passing through a sieve screen with a mesh aperture of 710 μmin accordance with the herein defined British Pharmacopoeia test fordispersible tablets.

Preferably the disintegrating time of a tablet according to theinvention is less than 20 minutes, more preferably less than 18 minutesand most preferably less than 20 minutes, still more preferably 12 to 20minutes.

Furthermore the disintegrating times and relatively fine dispersionsobtained with tablets according to the invention are also advantageousregarding the phosphate absorption capabilities. Thus tablets accordingto the invention can be presented for disintegrating in water or in theoral cavity as chewable tablets and also for directly swallowing. Thosetablets according to the invention that are intended to be swallowed arepreferably film-coated to ease application.

The present invention also concerns the use of particles comprising aphosphate binder, especially particles comprising sucroferricoxyhydroxide for the preparation of a of a pharmaceutical composition,in particular a compressed or a directly compressed tablet, wherein atleast 40%, preferably 60%, most preferably 80% even more preferably 90%(by volume), of the particles, especially of the sucroferricoxyhydroxide particles in the a particle size distribution are between 4to 200 μm or preferably between 5 to 160 μm or in between 21 to 160 μm.

The present invention also concerns the use of particles comprising aphosphate binder, especially particles comprising sucroferricoxyhydroxide for the preparation of a compressed or a directlycompressed tablet, wherein the phosphate binder has a d50 in theparticle size distribution of between 40 μm to 80 μm or between 42 μm to75 μm.

The present invention also concerns the use of particles comprising aphosphate binder, especially sucroferric oxyhydroxide for thepreparation of a pharmaceutical composition or a compressed or adirectly compressed tablet, wherein;

-   -   i) the phosphate binder has a d50 in the particle size        distribution of between 30 μm to 120 μm, or 35 μm to 110 μm, or        40 μm to 108 μm, or 40 μm to 100 μm, or preferably of between 40        μm to 80 μm or between 42 μm to 75 μm, and/or    -   ii) at least 40%, preferably 60%, most preferably 80% even more        preferably 90% (by volume), of the sucroferric oxyhydroxide        particles have a particle size in the particle size distribution        of between 4 to 200 μm or preferably between 5 to 160 μm or        between 21 to 160 μm.

In a further preferred embodiment, the pharmaceutical composition is inthe form of a powder or of granules which can further be mixed with atleast one pharmaceutically acceptable excipient, most preferably in theform of a powder if the pharmaceutical formulation is directlycompressed into a tablet or used for granulation.

In a preferred embodiment, the used pharmaceutical formulationpreferably contains a lubricant, which is preferably magnesium stearate.

In addition to the active ingredient (phosphate binder particles), thepharmaceutical compositions (e.g. tableting powders or tabletinggranules) may contain a number of inert materials known as excipients(or pharmaceutically acceptable excipients). They may be classifiedaccording to the role they play in the final tablet. Excipients areselected to aid in the processing and to improve the properties of thefinal product, and may be classified according to the role they play inthe final tablet. They may include fillers, binders or diluents,lubricants, disintegrants and glidants. Other excipients whichcontribute to the physical characteristics of the finished tablet aree.g. coloring agents, and flavors in the case of chewable tablets.Typically, excipients are added to a formulation to impart good flow andcompression characteristics to the material being compressed. Suchexcipients and corresponding ranges are particularly described in theInternational Patent application WO2009/06993 A1. Typically not morethan 35% (by weight on a dry weight basis) of excipients are added tothe total of the pharmaceutical composition.

In a preferred embodiment, this invention concerns any of the hereindescribed pharmaceutical compositions, or compressed tablets preferablydirect compressed pharmaceutical tablets, wherein at least one of thepharmaceutically acceptable excipients is used in an amount of forexample 0.01% to 10% or 0.01% to 6% or 0.1% to 6% (by weight on a dryweight basis). In the most preferred embodiment of using sucroferricoxyhydroxide as the phosphate binder particles (consisting essentially(i.e. except impurities, i.e. generally more than 95 or 98 wt-%) ofiron(III)-oxyhydroxide stabilized by sucrose, and starches) as anadditional excipient only those selected from flavor, sweeteners ortaste-enhancing agents, glidants or lubricants, the latter beingpreferably selected from magnesium stearate or collodial silicas likeAerosil®, are used in an amount of at most 10%, preferably at most 6%,more preferably at most 3% (by weight on a dry weight basis).

In a preferred embodiment, this invention concerns any of the hereindescribed pharmaceutical compositions, or compressed tablets preferablydirect compressed pharmaceutical tablets, wherein at least one thepharmaceutically acceptable excipient is a lubricant preferablymagnesium stearate and a flavor agent.

One, two, three or more diluents or fillers can be selected as furtherpharmaceutically acceptable excipient. Examples of pharmaceuticallyacceptable fillers and pharmaceutically acceptable diluents include, butare not limited to, e.g. confectioner's sugar, compressible sugar,dextran, dextrin, dextrose, lactose, mannitol, microcrystallinecellulose, powdered cellulose, sorbitol, sucrose and talc. The preferreddiluents include e.g. microcrystalline cellulose. Microcrystallinecellulose is available from several suppliers. Suitable microcrystallinecellulose includes Avicel products, manufactured by FMC Corporation.Another diluent is e.g. lactose. The diluent, fillers, e.g., may bepresent in an amount from about 0.1% to 20% and about 0.5%-40%respectively by weight of the composition.

One, two, three or more disintegrants can be selected. Examples ofpharmaceutically acceptable disintegrants include, but are not limitedto, e.g. starches; clays; celluloses; alginates; gums; cross-linkedpolymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calciumcarboxymethylcellulose and cross-linked sodium carboxymethylcellulose;soy polysaccharides; and guar gum. The disintegrant, e.g., may bepresent in an amount from about 0.01% to about 10% by weight of thecomposition. A disintegrant is also an optional but useful component ofthe tablet formulation. Disintegrants are included to ensure that thetablet has an acceptable rate of disintegration. Typical disintegrantsinclude starch derivatives and salts of carboxymethylcellulose. Sodiumstarch glycolate is the preferred disintegrant for this formulation.

One, two, three or more lubricants can be selected. Examples ofpharmaceutically acceptable lubricants and pharmaceutically acceptableglidants include, but are not limited to, e.g. colloidal silica,magnesium trisilicate, talc, tribasic calcium phosphate, magnesiumstearate, aluminum stearate, calcium stearate, stearic acid,polyethylene glycol and glycerol behenate. The lubricant, e.g., may bepresent in an amount from about 0.01 to 10% or from 0.1% to about 6% byweight of the composition; whereas, the glidant, e.g., may be present inan amount from about 0.01 to 10% or about from 0.1% to about 10% byweight. Lubricants are typically added to prevent the tablet blend fromsticking to punches, minimize friction during tablet compression andallow for removal of the compressed tablet from the die. Such lubricantsare commonly included in the final tablet mix in amounts usually aroundor less than 2% by weight. The lubricant component may be hydrophobic orhydrophilic. Examples of such lubricants include e.g. stearic acid, talcand magnesium stearate. Magnesium stearate reduces the friction betweenthe die wall and tablet mix during the compression and ejection of thetablets. It helps prevent adhesion of tablets to the punches and dies.Magnesium stearate also aids in the flow of the powder in the hopper andinto the die. The preferred lubricant, magnesium stearate is alsoemployed in the formulation. Preferably, the lubricant is present in thetablet formulation in an amount of from about 0.01 to 10% or from about0.1% to about 6%; also preferred is a level of about 0.1% to about 4% byweight; and most preferably from about 0.1% to about 2% by weight of thecomposition. Other possible lubricants include talc, polyethyleneglycol, silica and hardened vegetable oils. In an optional embodiment ofthe invention, the lubricant is not present in the formulation, but issprayed onto the dies or the punches rather than being added directly tothe formulation.

In addition, tablets often contain diluents or fillers which are addedto increase the bulk weight of the blend resulting in a practical sizefor compression (often when the dose of the drug is smaller).

Conventional solid fillers or carriers are substances such as, e.g.cornstarch, calcium phosphate, calcium sulfate, calcium stearate,glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural orsynthetic gums, such as carboxymethyl cellulose, methyl cellulose,alginate, dextran, acacia gum, karaya gum, locust bean gum, tragacanthand the like, diluents, binders, disintegrating agent, coloring andflavoring agents could optionally be employed.

Binders are agents, which impart cohesive qualities to the powderedmaterial. Examples of pharmaceutically acceptable binders as excipientsinclude, but are not limited to, starches, sugars; celluloses andderivatives thereof, e.g., microcrystalline cellulose, hydroxypropylcellulose, hydroxylethyl cellulose and hydroxylpropylmethyl cellulose;sucrose; glucose, dextrose, lactose dextrose; corn syrup;polysaccharides; and gelatin. During the clinical trials, the applicanthas furthermore realized that the taste of the phosphate binder was notappreciated by the subjects and did directly affect the compliance withthe therapeutic treatment (treatment adherence). For sake of clarity itshould be noted that sucrose and starches being part of the activeingredient sucroferric oxyhydroxide or PA21 do not count as excipients,like binders, sweeteners, etc. listed here.

In further embodiment the formulations, compositions and tablets of theinvention comprise one or more flavoring or taste-masking and coloringadditives such as e.g., flavours, sweeteners, taste-enhancing agents,colorants, and the like, which are typically used for oral dosage forms.

In preferred embodiment the formulations, compositions and tablets ofthe invention comprise a flavouring agent with Woodberry flavour. TheWoodberry flavor provides better compliance and acceptance of theclaimed phosphate binder tablets.

Taste-masking agents, such as a taste-enhancing agent, flavouring agent,and/or natural or artificial sweetener, including intense sweetener, areincorporated into oral dosage forms, such as chewable dosage forms, togive them a more pleasant taste or to mask an unpleasant one.

Typical sweeteners as excipient include, but are not limited to, sugarslike e.g. sucrose, fructose, lactose, confectionery sugar, powderedsugar, or are polyols which is e.g. sorbitol (e.g. Neosorb), xyitol,maltitol, maltose and polydextrose, or a mixture thereof. Typicalintense sweeteners may include, but not be limited to, e.g. aspartame,sucralose, acesulfam K, and/or saccharin derivatives, or a mixturethereof. Further suitable sweeteners or taste-enhancing agents includeglycosides such as e.g. neohesperidin dihydrochalcone (neohesperidin DCor NHDC), glycyrrhizin, glutamate, and the like. The latter may be usedin very small quantities and thus may hereinafter also be calledtaste-enhancing agents. All the above are suitable to be used alone oras mixtures with other sweeteners and/or flavouring agents. Thesesubstances insure great lingering of the sweet taste and cover anyundesired aftertaste. Preferred sweeteners and/or taste-enhancing agentsinclude glycosides such as neohesperidin dihydrochalcone.

In one embodiment the sweetener of choice may be present in an amount of0.00001 to 2% (w/w), preferably 0.00001 to 0.1% (w/w), most preferably0.00001 to 0.001% (w/w), in relation to the total weight of thecomposition.

The taste-enhancing agent of choice may be present in an amount of 0.1to 50 ppm, preferably 1 to 10 ppm, most preferably 1 to 5 ppm, inrelation to the total weight of the composition. Typical flavoringagents include any natural and artificial flavoring agent suitable forpharmaceutical applications, such as flavoring agents derived from aspice, fruit or fruit juice, vegetable or vegetable juice, and the like,for example flavors based on cocoa, caramel, vanilla, apple, apricot,berry (e.g. blackberry, red currant, black currant, strawberry,raspberry, Woodberry, etc.), mint, panettone, honey, nut, malt, cola,verveine (verbena) or any combination thereof, such as for examplecaramel/vanilla, fruit/cream (e.g. strawberry/cream) and the like. Inone embodiment the flavoring agent of choice may be present in an amountof 0.01 to 12% (w/w), preferably 0.1 to 6% (w/w), most preferably 0.1 to4% (w/w), in relation to the total weight of the composition.

Additional examples of useful excipients are described in the Handbookof pharmaceutical excipients, 3rd edition, Edited by A. H. Kibbe,Published by: American Pharmaceutical Association, Washington D.C.,ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4^(th)edition), Edited by Raymond C Rowe-Publisher: Science and Practice whichare incorporated herewith by reference.

The above described formulations are particularly adapted for theproduction of pharmaceutical compositions e.g. tablets, compressedtablets or preferably direct compressed tablets, caplets or capsules andprovide the necessary physical characteristics, regarding e.g.dissolution and drug release profiles as required by state of the artdosage forms in the field. Therefore in an additional embodiment, thepresent invention concerns the use of any of the above describedpharmaceutical compositions, tablets, chewable tablet, granules, capletsor capsules in particular for granulation, direct compression and drygranulation (slugging or roller compaction).

The above compositions are also particularly useful for the productionof tablets especially compressed tablets and very preferably directcompressed tablets e.g. chewable tablets.

The tablets obtained with the above described compositions especiallywhen processed in the form of direct compressed tablets or the hereindescribed direct compressed tablets, exhibit preferable friabilityproperties very good breaking strength, improved manufacturingrobustness, optimal hygroscopicity, hardness, compressibility,chewability, low residual water content especially for direct compressedtablets, short Disintegration time DT (less than 30 minutes) accordingto the British Pharmacopoeia 1988, resulting in a fine dispersion with apreferable particle size distribution after disintegration. Although,the Disintegration time DT values claimed in the present applicationhave been obtained according to the European Pharmacopoeia (EP)04/2011:20901 defined methodologies.

Preferably the hereinabove described compressed tablets (e.g. directcompressed tablets), have a disintegration time less than 30 minutes,preferably between 5 and 20 minutes.

Preferably for the hereinabove described compressed tablets (includingdirect compressed tablets) have a tablet hardness of comprised between70 N to 250 N or between 80 to 200 N, preferably between 100 N to 230 N,and a friability of between 0% to 7% or 0.5 to 7%.

This present invention of direct compression of phosphate bindersespecially sucroferric oxyhydroxide involves blending and compression.The choice of grades of excipients added in particular to the claimedsucroferric oxyhydroxide particles, takes the particle size range of thesucroferric oxyhydroxide particles into consideration to be maintainedwithin a range that allows homogeneity of the powder mix and contentuniformity of the phosphate binder particles especially sucroferricoxyhydroxide particles in the final dosage form, and as explained beforethe particle size distribution of the selected further excipientscomprised in the pharmaceutical formulation or a pharmaceuticalcomposition or tablets is preferably similar to the particle sizedistribution of the phosphate binder particles preferably thesucroferric oxyhydroxide particles. This prevents segregation of theparticles in the hopper during direct compression. The advantages ofusing the claimed pharmaceutical compositions are that they impartcompressibility, cohesiveness (reducing it) and flowability (increasingit) of the powder blend. In addition, the use of direct compressionprovides competitive unit production cost, shelf life, eliminates heatand moisture, allows for prime particle dissociation, physical stabilityand ensures particle size uniformity.

The described advantages of the claimed pharmaceutical compositions arealso very useful for e.g. roller compaction or wet granulation or tofill sachets or capsules.

In a further embodiment, the herein described and claimed pharmaceuticalcompositions and tablets (e.g. direct compressed tablets) contain one ormore further phosphate binder preferably one or two further phosphatebinders.

Preferred further phosphate binders are especially organic polymers suchas e.g. sevelamer hydrochloride. Management of the phosphorus level isone of the primary treatments for CKD-MBD using phosphate binders toreduce the serum phosphate concentration. Sevelamer is marketed underthe brand name Renagel® (hydrochloric acid) and Renvela® (Carbonateformulation) by Genzyme.

Other Phosphate binders that may be used include in particular calcium,magnesium, aluminum, iron, lanthanum and bismuth salts, whose which arebetter soluble than the corresponding phosphate salts of these cations.In addition, phosphate-binding organic polymers having an anionexchanger function such as AMG 223 (Amgen) and MCI-196 (Colestilan,Mitsubishi) are suitable substances for the invention. Suitable aluminumsalts include all the pharmaceutically tolerable salts which fulfill theabove requirements, especially oxides, in particular algedrate and/orhydroxides. All the pharmaceutically acceptable salts which fulfill theabove requirements, in particular lanthanum carbonate including itshydrates are suitable as the lanthanum salts. All the pharmaceuticallyacceptable salts which fulfill the above requirements, preferablychlorides, sulfates, hydroxides, oxides, carbonates and in particularheavy magnesium carbonate are suitable as the magnesium salts. Preferredphosphate binders based on metal salts are for example, fermagates andcalcium salts, preferably calcium carbonate and/or calcium chloride andespecially preferably calcium acetate.

The present invention also covers any of the herein above claimedpharmaceutical compositions or tablets comprising a second phosphatebinder selected from e.g. any of Sevelamer hydrochloric acid formulation(Renagel®), Sevelamer Carbonate formulation (Renvela®), calcium,magnesium, aluminum, iron, lanthanum salts and bismuth salts.

EXPERIMENTAL SECTION Example 1

The tablets prepared as herein above described can be tested as follows.

Tablet Evaluation Methods

1. Average tablet weight. Twenty tablets are weighed on an analyticalbalance and the average tablet weight calculated.

2. Tablet breaking strength N. 5 tablets are individually tested using aSchleuniger crushing strength tester, and the average breaking strengthcalculated.

3. Friability (% loss). 10 tablets, accurately weighed, are subjected to10 minutes friability testing using a Roche Friabilator (as describedand measured under the conditions of example 4(C)). The tablets arededusted, reweighed, and the weight loss due to the friability iscalculated as a percentage of the initial weight. The friability dataand values claimed in the present application have been measuredaccording to the European Pharmacopeia's 01/2010:20907 with a Rochefriabilator.

4. Disintegration time DT (as defined in the European Pharmacopoeia04/2011:20901). 6 tablets are tested in accordance to the above-definedEP test.

5. Dispersion Quality. In accordance with the BP uniformity ofdispersion test for dispersible tablets (BP 1988 Volume II page 895),two tablets are placed in 100 ml of water at 19-21° C. and allowed todisperse.

Granule Evaluation Methods

1. Loss on Drying (LOD). The residual moisture content of the granule(LOD) can be determined on a 3-4 g sample using a Mettler moistureanalyser set at 105° C. for 10 min. operated in accordance with themanufacturer's procedure.

2. Particle size distribution (PSD). A 20 g sample of sucroferricoxyhydroxide as the phosphate binder is analyzed with a laser particlesize analyzer Beckman Coulter LS 13 320 equipped with a dry powdersystem, thereby relying in particular on the corresponding “LS 13 320Laser Diffraction Particle Size Analyzer Instructions For Use PNB05577AB (October 2011)” using in particular the complete Mie theory.These laser diffraction analytical technologies yield volume weighteddistributions (see e.g. FIG. 2). A run length of approx 13″ and anobscuration of 4% is applied. The PSD is calculated from the cumulativevolume percentage undersize size distribution using a computer program.

Example 2: Improved Manufacturing Robustness

A preliminary compactibility assessment is carried out on a Kilian pressusing different formulations of sucroferric oxyhydroxide with differentexcipients e.g. magnesium stearate.

Data demonstrate that our claimed pharmaceutical compositions on beingcompressed with increasing levels of pressure (compression force) show asubstantially useful increase in tablet strength. In particular e.g.mixture of sucroferric oxyhydroxide with magnesium stearate show asubstantially useful increase in tablet strength if sucroferricoxyhydroxide is within the hereinabove claimed particle sizedistribution. These results indicated that from compressibility point ofview the claimed formulations provide a clear improvement. Withincreasing pressure (compression force) our claimed formulations show asubstantially useful increase in tablet strength.

A compressibility study is carried out on an instrumented Fette 102ipress with force and displacement sensors on both upper and lowerpunches.

A clear indication is afforded from these data that sucroferricoxyhydroxide tablets are very likely to have poor tablethardness/crushing strength unless proper particle size are selected. Ourclaimed formulations are particularly adapted to provide the requiredcompactibility.

Example 3: Friability

Evaluation can alternatively be carried out using a Fette 2200 press at6 different settings: strain rate settings of 30′000 to 70′000 tabletper hour) and main compression force of 35-55 kN. The trials useFlat-faced Beveled-edge (FFBE) tooling of 20 mm diameter for 2577.5 mgtablets (other diameters are used depending on the weight of the testedtablet). The friability data and values claimed in the presentapplication have been measured according to the European Pharmacopeia's2.9.7 with a Roche friabilator. Total tablet weights were selected sothat both the 20 mm FFBE tablets would have 2500 mg of sucroferricoxyhydroxide and identical tablet thickness. Friability, Compressionprofile, Strain rate profile and Weight variation are the measuredoutcomes. Study design and the friability results obtained from thestudy are used to determine the variables (particle size distribution inthe formulation, tablet weight, tablet thickness and weight, watercontent in the tablet etc) impacting the outcome of hardness.

Example 4: Particle Size Distribution Measured by Laser Diffraction

The sucroferric oxyhydroxide particle size distribution having particlesin the range of 1 to 200 μm or 4 to 200 μm or 5 to 160 μm or between 21to 160 μm, or with a d50 in the particle size distribution or between 30μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 100 μm, or preferably ofbetween 40 μm to 80 μm or between 42 μm to 75 μm, and which isparticularly adapted to produce the herein described formulationsespecially the direct compressed tablets, can be produced as describedbelow.

The methods and values describe in the below example 4, are the basissupporting the values included in the present claims.

1. Preparation of Particle Size Distribution Via a SucroferricOxyhydroxide Applied for Direct Compression Tablets.

The applicant has discovered a particle size distribution (e.g. havingparticles mainly (e.g. more than 50 volume-%) between 10 to 152 μm) ofin particular sucroferric oxyhydroxide (or with a d50 of the particlesize distribution of between 40 μm to 80 μm or preferably between 42 μmto 75 μm), which is particularly suitable for direct compression tabletsof phosphate binders.

Improved results are obtained with a d50 of the particle sizedistribution of between 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to108 μm, or 40 μm to 100 μm, or preferably between 40 μm to 80 μm orpreferably between 42 μm to 75 μm.

The particle size distribution determined by laser light diffractionmethod is preferably specified as follows: d10 larger or equal 5 μm, d50larger or equal 35 μm, preferably between 40 μm to 80 μm or between 42μm to 75 μm and d90 less or equal 380 μm. Particle size have beenmeasured by laser diffraction.

Equipment:

Measuring device: e.g. LS 13 320 Laser Diffraction Particle SizeAnalyzer of Beckmann Coulter, Beckman Coulter International S.A.Switzerland

Sample module: Vacuum pressure dispersion system, e.g. Dry Powder System(Tornado), Beckman Coulter International S.A. Switzerland

Conditions:

Average vacuum: 25-30″ H₂O; Obscuration approx. 48-10%; Run lengthapprox. 25 seconds’.

Procedure:

Introduce 20 g of the sample into the Dry Powder dispersion System.

Measurement: Apply the specified vacuum to transfer the sample anddetermine the cumulative volume distribution using a laser lightdiffraction instrument in accordance with the instruction manual. Theparameters may be adjusted so that the test dispersion isrepresentative, homogeneous and well dispersed.

Evaluation/assessment: Determine the particle sizes at the undersizevalues of 10%, 50% and 90% (d10, d50, d90), and additional values inquestion, from the cumulative volume distribution.

The inventive particle size distribution (in particular the sucroferricoxyhydroxide particle size distribution) can be obtained by the belowdescribed process, which is a none-limitative example. Alternativeprocesses can easily be implemented by the person skied in the art.

A. Manufacturing Process.

The sucroferric oxyhydroxide drug substance is basically prepared asdescribed in the European Patent WO9722266A1 or in the patentapplication WO2008/062993.

The manufacturing process for the sucroferric oxyhydroxide drugsubstance (named PA21 in the below FIG. 1) yields a stabilizedpolynuclear β-iron(III)-oxyhydroxide with a particularly high phosphateadsorption capacity that is maintained during long-term storage.

A flow chart of the manufacturing process is provided in below. Itcomprises the following steps:

-   -   Synthesis of iron(III)-oxyhydroxide by precipitation of an iron        salt (e.g. iron(III)-chloride) with a base (sodium carbonate        which was found to be the best choice). The process was        optimised by keeping the addition of iron(III)-chloride and the        stirring rate adjusted.    -   Desalination: Excess sodium chloride formed is removed by means        of a washing step with water.    -   Addition of starches and sucrose to the iron(III)-oxyhydroxide        suspension in a relative mass ratio of starch to sucrose to iron        of preferably 1.5:1.5:1 under constant stirring. This step is        performed in order to stabilise the iron(III)-oxyhydroxide and        to allow further processing.    -   Spray drying under controlled conditions as described above.

The resulting sucroferric oxyhydroxide drug substance can be obtainedwith the desired particle size distribution by adapting the spray dryingsettings as described above in particular using a centrifugalatomization unit. By spray drying, the different settings of theatomizer in the spray dryer are selected to obtain the desired particlesize distribution. This technique is known by the person skilled in theart and settings can depend on the used spray dryer equipment andsuitably adapted. Optionally, the obtained resulting sucroferricoxyhydroxide drug substance can be further processed to obtain thedesired particle size distribution by other well-known techniques suchas by mechanical stress.

FIG. 2 shows the Particle Size Distribution of the obtained PA21 DrugSubstance resulting from spray drying process and analyzed using a LS 13320 Laser Diffraction Particle Size Analyzer of Beckmann Coulter.

B. Mechanical Stress

Basically the phosphate absorber particles in the desired particle sizerange can be also obtained by mechanical stress. This stress can bemediated by impact, shear or compression. In most commercially availablegrinding equipment a combination of these principles occurs. For thesucroferric oxyhydroxide obtained by the above described manufacturingprocess preferably a mechanical impact or jet mill might be used apartfrom the preferred spray drying process. The most preferable mechanicalimpact mill can be equipped with different kind of beaters, screens,liners or with pin plates. For our process an impact mill with platebeater and a slit screen 5*2.5 cm is used. The impact speed should bevariable between 20 and 100 m/s (as peripheral speed) to adapt to anybatch to batch variation. A peripheral speed of the beater of about40-50 m/s is used.

Good results (particle size distribution) can also be obtained bymechanical stress e.g. roller compaction, milling and/or sieving.

Other techniques as described in the art and commonly used by the personskilled in the art can also be used to obtain targeted particle sizerange.

In order to evaluate the compressibility of API (Active PharmaceuticalIngredient: sucroferric oxyhydroxide) batch with different particle sizedistribution different API batch covering the range from approximately40 μm to 110 μm were selected.

Characteristics of the Selected Sucroferric Oxyhydroxide API Batches:

Batch number 030609-02 070609-01 090609-01 110709-01 Iron content [%]20.95 20.66 20.53 22.08 LOD [% m/m] 6.07 6.07 6.46 5.34 Particle sizedistribution [μm] d10 25.29 17.69 16.76 10.64 d50 109.3 65.53 75.1042.85 d90 207.2 135 151.6 96.89 Bulk density [g/ml] 0.85 0.85 0.8340.894 Tapped density [g/ml/] 1.013 1.013 0.963 1.011 Hausner factor1.1919 1.1919 1.1538 1.1313 Respose angle 20.25° 20.25° 18.68° 21.33°Powder flow [g/s] 32.95 32.95 34.08 27.86

All API batch presented similar flowability, density and LOD. Thevariability of iron content was in the usual range for this kind ofproduct. The major difference was only the particle size distribution.

C. Tablet Compression

Equipment:

Tabletting press: Rotative Killian E 150 equipped with 20 mm flat facedpunches

Tablet hardness: 5 tablets are individually tested using a Schleunigercrushing strength tester, and the average breaking strength calculated.The tablet hardness is measured according to the European Pharmacopoeia01/2008:20908.

Tablet thickness: 5 tablets are individually measured with a calliperand the average thickness is calculated

Tablet friability: friability is measured according to the EuropeanPharmacopeia's 01/2010:20907 with a Roche friabilator

Mean mass: 10 tablet are weighted and the mean mass is calculated

Disintegration (as defined in the European Pharmacopoeia 04/2011:20901)are carried out with standard equipment (Sotax DT3 disintegrationtester) on 6 tablets

1. Preparation of the Pharmaceutical Formulation Powders.

The different API batches (with the different particle size ranges) wereall formulated with the following composition (pharmaceuticalformulation) in the form of a powder comprising the sucroferricoxyhydroxide particles:

Component Composition per tablet: Function [mg] PA21-2 powder⁽¹⁾ Active2,500.00 corresponding to iron ingredient 500.00 Woodberry flavourFlavour 40.00 Neohesperidin dihydrochalcone Sweetener 0.01 Magnesiumstearate Lubricant 25.00 Silica (colloidal, anhydrous) Flow aid 12.49Total N/A 2,577.50 ⁽¹⁾Iron(III)-oxyhydroxide, sucrose, potato starch,pregelatinised starch (sucroferric oxyhydroxide).

2. Preparation of the Compressed Tablets.

Following equipment were used for the preparation of the blend:

Tumbling blender (Röhnrad Engelsmann), Quadro comill 193

Magnesium stearate, silica and neohesperidin DHC were purchased of PhEurquality. The selected flavours are standard flavours used for food andpharmaceutical product.

An identical manufacturing process by direct compression was applied toall API batch to compare their processability. The manufacturing processconsisted of:

-   -   Sieving and blending of all ingredients    -   Lubrication by the addition of magnesium stearate    -   Tabletting into biplanar tablets with 20 mm diameter on a        rotating tablet press

The tablet weight was adjusted according to the drug substance assay toprovide a nominal dosage of 500 mg iron i.e. 2500 mg of sucroferricoxyhydroxide.

Tabletting trials were performed in order to optimize the hardness ofthe tablet. For such a 20 mm tablet a hardness of at least 100 N isnecessary to able filling of the tablet in standard packaging withoutbreak of damage of the tablet.

Following tableting trials were done:

Tabletting trials E222X380 E222X381 E222X382 E222X382B E222X383E222X383B Batch Nr API 070609-01 030609-02 090609-01 090609-01 110709-01110709-01 Hardness [N] 106 83 93 121 88 140 Mean mass [mg] 2588 25362570 2575 2542 2525 Thickness [mm] 6.31 5.89 6.39 6.26 6.24 6.10Friability [%] 6.87 10.82 6.84 4.05 6.53 3.50 Disintegration [%] 9.2319.51 8.81 13.52 6.28 9.18

Based on the knowledge in the art, for a big tablets like the developedhigh load direct compressed tablets (i.e. 2500 mg of sucroferricoxyhydroxide), the ideal d50 should have been between 200 to 350 μm.Nobody would have expected that the claimed small sucroferricoxyhydroxide particle size could have resulted in improved tablet(direct compressed high load tablets) i.e. improved physical properties.

Surprisingly the sucroferric oxyhydroxide particles, with a d50 of 109μm (batch no. 030609-02) could not yield in tablet with the mostfavorable targeted hardness while still acceptable. A maximum of 83 Nwas reached on the tablet press at this point the compression force wasalready maximal and the noisy sound of the machine oblige us to stop theexperiment to not damage the press. Although the tablet was compressedat the lowest thickness we obtained the lowest hardness. The tablettingtrials E222X383B with a d50 of 43 μm and E222X382B with a d50 of 75 μmallowed surprisingly to increase the compression force resulting intothe increase of the hardness, which was not the case with e.g. batcheswith a d50 of 109 μm. With such batches (d50 of >109 μm) whatever theused compression force is, it was not possible to obtain tablets withimproved hardness. Therefore a d50 of around 109 μm is a upper limitzone of what is still acceptable. So a reasonable upper limit is in thezone of 110 or 120 μm. At 120 μm, the hardness shall be around 80 N orslightly lower than 80 N.

Trials performed with sucroferric oxyhydroxide particles with a d50 inthe range of 42 to 75 μm revealed a surprisingly good compressibility ofthe material and allowed to target up to 140 N of hardness.

Sucroferric oxyhydroxide particles with a d50 less than around 42 μmwere considered as less appropriate for tableting as they would resultin too much loss of material in a rotating tableting machine.

Based on the experimental evaluations, the hereinabove claimedimprovements are observed with sucroferric oxyhydroxide particles havinga d50 between 30 μm and 120 μm or a d50 between 35 μm and 110 μm. Thebest results are observed with sucroferric oxyhydroxide (API) particleshaving a d50 between 40 μm to 108 μm, 40 μm and 100 μm or preferablybetween 40 μm and 80 μm.

FIG. 3 demonstrates that the sucroferric oxyhydroxide (API) particleswith a d50 between 40 and 80 μm is particularly preferred to get aminimum of 100 N.

The disintegration time obtained with the sucroferric oxyhydroxideparticles with a d50 of 109 μm (batch 030609-02) for tablet of 83 N was300% higher (19′51″) than tablet of similar hardness (88N) obtained withan API with a d50 of 42 μm (110709-01) that disintegrate in 6′28″. Suchdifference could impact the dissolution time of the tablet and is lessfavourable.

To confirm the excellent compressibility of the sucroferric oxyhydroxideparticles the compression profile has been investigate on an additionalbatch with a d50 of 50.3 μm

The tablet batch 1260111 has been produced on a rotating tabletingmachine gave following results:

Tablet thickness [mm] 6.22 6 6.04 5.85 5.82 Hardness [N] 78 113 132 154187 Compression force [kN] 37 40 45.6 48.7 50.6 Friability [%] 1.2 0.40.1 0.1 0.2 (with abrasion wheel)

As shown in FIG. 4 the sucroferric oxyhydroxide particles with a d50 of50 μm showed very good compression properties and show a linear increaseof the hardness in function of the force. Tablet up to 187 N could bemanufactured.

Example 5: Alternative Studies to Test the Chewability of the CompressedChewable Tablets of the Invention

The pharmacopoeia tests of (diametrical or radial) hardness (resistanceto crushing Ph.Eur. 2.9.8), friability (Ph.Eur. 2.9.7) anddisintegration (Ph.Eur. 2.9.1) are carried out with standard equipment(Erweka TBH 220 hardness tester, Erweka TA 120 friability tester withstandard drum and abrasion drum (or Roche friabilator), and Sotax DT3disintegration tester). To avoid any confusion, it is emphasized thatthe friability values claimed in the present application have beenmeasured according to the European Pharmacopeia's 01/2010:20907 with aRoche friabilator, that the disintegration values claimed in the presentapplication have been measured according to the European 04/2011:20901are carried out with standard equipment (Sotax DT3 disintegrationtester), and the tablet hardness values claimed in the presentapplication have been measured using a Schleuniger crushing strengthtester, i.e. conditions as described in example 4 according to theEuropean Pharmacopeia's 01/2008:20908.

In addition, axial hardness (ring and tube test), grinding properties(plate test) are also measured using the texture analyzer (TAXt2i®Texture Analyser Stabel Micro Systems Ltd, Godalming, UK), used tomeasure the texture of a wide variety of materials. In addition, theKramer shear cell, from Instron High Wycombe, UK ( ), used in the foodindustry to provide information on bite characteristics, crispness andfirmness, and a Typodont D85SDP-200 Model from Kilgore InternationalInc., Coldwater, Mich., USA ( ) are also used in this study to test thechewability of tablets. The load was applied to the Typodont Model bythe texture analyzer, which means that the Typodont model is anaccessory to the texture analyzer in the tests carried out here.

The following test is carried out with both dry and artificial salivawetted tablets.

The artificial saliva was prepared according to the modified recipe ofKlimek (1982) (Original: Matzker and Schreiber (1972)):

Ascorbic acid 0.002 g/l Glucose 0.030 g/l NaCl 0.580 g/l CaCl₂ 0.170 g/lNH₄Cl 0.160 g/l KCl 1.270 g/l NaSCN 0.160 g/l KH₂PO₄ 0.330 g/l Urea0.200 g/l Na₂HPO₄ 0.340 g/l Mucine 2.700 g/l

The prepared solution (500 ml) was kept refrigerated (4-6° C.) becauseof its limited shelf life.

Ring Test

In this test, the plastic tool simulates teeth being loaded onto atablet, with the ring simulating the lower mandible. The ring test isclose to an actual biting event.

The ring external diameter d_(a) is 20 mm. The inner diameter, andconsequently the diameter of the central cavity d_(i) is 14 mm, sincethe metal of the ring has a thickness of 3 mm. The plastic tool withrounded site of contact is a standard component of the texture analyser.The speed of descent of the plastic tool was 2 mm/sec. The distancetravelled is set at 5 mm with a load cell of 50 KG and the textureoperation mode is “return to start”.

In addition, the ring test is essentially an axial breaking strength.The tablet rests on the ring. The force, F_(max), where breakage occursis noted. The energy exerted (area under the force-displacement curve,is calculated. The test is carried out on dry tablets and wet (wet byimmersion by means of a tweezers in artificial saliva for 10 seconds).

Plate Test

The plate test measures the depth of penetration by the application ofmaximum force for repeated loadings, and thus simulates the effect ofteeth penetration during repeated chewing actions.

Here, the tablet is placed on the grooved reverse side of the base plateof the texture analyzer and a force is repeatedly exerted on the tabletto simulate repeated chewing actions.

The texture analyzer test settings were “cycle until count mode”, with aload intensity chosen which does not cause the tablet to break (35 N fora rate of descent of 0.2 mm/sec). The approaching rate (pre-test speed)was 0.5 mm/sec for increased sensitivity. The applied force at which thetexture analyser should begin the actual measurement is set at 0.0493 Nwith what is called the trigger. A typical force-displacement curve for10 cycles is shown. The plate test measures the depth of penetration bythe application of maximum force for repeated loadings.

Other tests such as the Tube test, Kramer shear cell test or Typodontmodel test can be performed.

Conclusion:

The texture tester in the ring test mode (yielding axial breakingstrengths) is considered to best characterize the chewability featuresof the sucroferric oxyhydroxide direct compressed tablets of the presentinvention. The test confirms the chewability quality of the tablets ofthe invention.

A number of tests are evaluated in order to provide in vitro evidence ofthe chewability quality of a chewable tablet. The results are comparedwith those of two commercially available chewable tablets.

Of the tests which more closely mirror actual chewing action, thetexture analyzer in the plate test mode was considered to be the mostreliable, especially with tablets wetted with artificial salvia provedto be the most discriminatory and useful. Those sucroferric oxyhydroxidetablets produced within the target radial hardness of ca. 130 Nperformed well in this test and even the variant 14I (radial hardness231.2 N) showed good chewable properties, confirming a shelf life limitof 230 N as suitable.

Sucroferric oxyhydroxide tablets within the target radial hardness limitexhibited chewability properties closely approaching those of the bestnon-phosphate binder product (Tablets A—Calcimagon®) and superior tobest phosphate binder competitor (Tablets B—Fosrenol®) in these tests.

For patient compliance it is an advantage that the chewable tabletsdisintegrate if chewing for whatever reason is incomplete and that thetablet robustness is sufficient to allow proper handling and transport.Sucroferric oxyhydroxide tablets variants meet this requirement.

Preferred Embodiments of the Invention

The following summarizes particular preferred embodiments of theinvention:

1. Embodiment

A compressed tablet, comprising the phosphate binder, said phosphatebinder comprises particles having a particle size distribution withparticles in the range of 4 to 200 μm. Preferably the phosphate binderconsists of such particles.

2. Embodiment

A compressed tablet according to embodiment 1, comprising the phosphatebinder, said phosphate binder comprises particles having a particle sizedistribution, wherein at least 40% of the particles have a particle sizewithin the range of 4 to 200 μm.

3. Embodiment

A compressed tablet, comprising the phosphate binder, said phosphatebinder comprises particles, having a particle size distribution, whereind50 is in the range of 40 μm to 80 μm.

4. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder comprises iron(III)-oxyhydroxide.

5. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder comprises iron(III)-oxyhydroxide and atleast one carbohydrate.

6. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder comprises iron(III)-oxyhydroxide andsucrose.

7. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder comprises iron(III)-oxyhydroxide, sucroseand at least one starch.

8. Embodiment

A compressed tablet according to any of the previous embodiments, whichcontains phosphate binder particles, especially of sucroferricoxyhydroxide, and at least one further pharmaceutically acceptableexcipient, and wherein at least 40%, or at least 60%, or at least 80%,or at least 90% of the particles in the phosphate binder particle sizedistribution in the tablet are between 4 to 200 μm, or between 5 to 160μm, or between 21 to 160 μm.

9. Embodiment

A compressed tablet, which comprises phosphate binder particles,especially of sucroferric oxyhydroxide and at least one furtherpharmaceutically acceptable excipient, and wherein the phosphate binderparticles have a particle size distribution with a d50 between 30 μm to120 μm, or 35 μm to 110 μm, or 40 μm to 100 μm, or preferably between 40μm to 80 μm or between 42 μm to 75 μm.

10. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder particles have a particle size distributionwith a d50 between 30 μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 100μm, or preferably between 40 μm to 80 μm or between 42 μm to 75 μm.

11. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the phosphate binder particles have a particle size distributionwith a d50 between 40 μm to 80 μm and wherein at least 60%, or at least80% of the particles of the phosphate binder particle size distributionin the tablet are between 4 to 200 μm or between 5 to 160 μm or inbetween 21 to 160 μm.

12. Embodiment

A compressed tablet, according to any of the previous embodiments,wherein: the phosphate binder particles have a particle sizedistribution with a d50 between 30 μm to 120 μm, or 35 μm to 110 μm, or40 μm to 100 μm, or preferably between 40 μm to 80 μm or between 42 μmto 75 μm, and/or the hardness of the tablet is between 70 to 250 N,and/or the tablet friability is between 0% to 7% or between 0.05% to 7%,and/or the tablet has a disintegration time less than 30 min, or ofbetween 5 to 20 min, and/or the tablet diameter is between 16 mm to 30mm, the tablet weight is between 1500 mg to 3000 mg (preferably 2000 to3000 mg) and the tablet thickness is between 4.5 mm and 7.5 mm.

13. Embodiment

A compressed tablet, according to any of the previous embodiments,wherein:

-   -   i) at least 40%, or at least 60%, or at least 80%, or at least        90% of the particles in the phosphate binder particle size        distribution in the tablet are between 4 to 200 μm or between 5        to 160 μm or between 21 to 160 μm, and    -   ii) the phosphate binder particles have a d50 in the particle        size distribution between 30 μm to 120 μm, or 35 μm to 110 μm,        or 40 μm to 100 μm, or preferably between 40 μm to 80 μm or        between 42 μm to 75 μm, and    -   iii) the hardness of the tablet is between 70 to 250 N, and    -   iv) the tablet friability is between 0% to 7% or between 0.05%        to 7%, and v) the tablet has a disintegration time of less than        30 min, preferably between 5 to 20 min, and    -   vi) the tablet diameter is between 16 mm to 30 mm, the tablet        weight is between 1500 mg to 3000 mg and the tablet thickness is        between 4.5 mm to 7.5 mm.

14. Embodiment

A compressed tablet, according to any of the previous embodiments,wherein;

-   -   i) at least 60%, or at least 80%, or at least 90% of the        particles in the phosphate binder particle size distribution in        the tablet are between 5 to 160 μm, and    -   ii) the phosphate binder particles have a d50 in the particle        size distribution between 30 μm to 120 μm, or 35 μm to 110 μm,        or 40 μm to 100 μm, or preferably between 40 μm to 80 μm, and/or    -   iii) the hardness of the tablet is between 70 to 250 N, and/or    -   iv) the tablet friability is between 0% to 7% or between 0.05%        to 7%, and/or v) the tablet has a disintegration time of less        than 30 min, preferably between 5 to 20 min, and/or    -   vi) the tablet diameter is between 16 mm to 30 mm, the tablet        weight is between 1500 mg to 3000 mg (preferably 2000 to 3000        mg) and the tablet thickness is between 4.5 mm and 7.5 mm,        and/or    -   vii) the tablet contains between 800 mg to 3000 mg of        sucroferric oxyhydroxide.

15. Embodiment

A compressed tablet according to any of the previous embodiments,wherein:

-   -   viii) at least 80%, or at least 90% of the particles in the        sucroferric oxyhydroxide particle size distribution are between        4 to 200 μm or in between 5 to 160 μm, and    -   ix) the sucroferric oxyhydroxide particles have a d50 in the        particle size distribution between 30 μm to 120 μm, or 35 μm to        110 μm, or 40 μm to 100 μm, or preferably between 40 μm to 80        μm, and    -   x) the hardness of the tablet is between 70 to 250 N, and    -   xi) the tablet friability is between 0% to 7% or between 0.05%        to 7%, and xii) the tablet has a disintegration time of less        than 30 min, or of between 5 to 20 min, and    -   xiii) the tablet diameter is between 16 mm to 30 mm and the        tablet weight is between 1500 mg to 3000 mg or in between 2000        mg to 3000 mg and the tablet thickness is between 4.5 mm to 7.5        mm, and    -   xiv) the tablet contains between 1500 mg to 3000 mg of        sucroferric oxyhydroxide.

16. Embodiment

A compressed tablet according to any of the any of the previousembodiments, which is a direct compressed pharmaceutical tablet.

17. Embodiment

A pharmaceutical formulation or a pharmaceutical composition, whichcontains phosphate binder particles comprising especially sucroferricoxyhydroxide and at least one further pharmaceutically acceptableexcipient, and wherein the phosphate binder particles have a d50 in theparticle size distribution of the phosphate binder particles between 40to 105 μm, 40 to 100 μm, 40 μm to 80 μm or in between 42 μm to 75 μm.

18. Embodiment

A pharmaceutical formulation or a pharmaceutical composition, whichcontains phosphate binder particles comprising especially sucroferricoxyhydroxide and at least one further pharmaceutically acceptableexcipient, and wherein at least 40%, or at least 60%, or at least 80%,or at least 90% of the phosphate binder particles in the particle sizedistribution are between 4 to 200 μm or between 5 to 160 μm or between21 to 160 μm.

19. Embodiment

A pharmaceutical formulation or a pharmaceutical composition, accordingto embodiments 17 or 18, wherein at least 40%, or at least 60%, or atleast 80%, or at least 90% of the phosphate binder particles in theparticle size distribution are between 4 to 200 μm or between 5 to 160μm or between 21 to 160 μm.

20. Embodiment

A tablet or pharmaceutical composition, according to any of the previousembodiments, wherein the phosphate binder particles especially thesucroferric oxyhydroxide phosphate binder particles, represent more than65%, or more than 80%, or more than 90%, or more than 95% of the totalweight of the tablet or of the pharmaceutical composition (by weight ona dry weight basis).

21. Embodiment

A tablet, a pharmaceutical formulation or a pharmaceutical composition,according to any of the previous embodiments, which comprises more than65%, or more than 80%, or more than 90%, or more than 95%, or more than98% of sucroferric oxyhydroxide particles, by weight on a dry weightbasis.

22. Embodiment

A compressed tablet according to any of the previous embodiments,wherein;

-   -   xv) the phosphate binder is sucroferric oxyhydroxide,    -   xvi) at least 80%, or at least 90% of the sucroferric        oxyhydroxide particles in the sucroferric oxyhydroxide particle        size distribution are between 4 to 200 μm or between 5 to 160        μm,    -   xvii) the sucroferric oxyhydroxide particles have a d50 in the        sucroferric oxyhydroxide particle size distribution between 30        μm to 120 μm, or 35 μm to 110 μm, or 40 μm to 100 μm, or        preferably between 40 μm to 80 μm,    -   xviii) the tablet contains between 800 mg to 3500 mg or between        1500 to 3500 mg of sucroferric oxyhydroxide,    -   xix) the sucroferric oxyhydroxide phosphate binder particles        represent more than 80%, or more than 90% of the total weight of        the tablet (by weight on a dry weight basis).

23. Embodiment

A compressed tablet according to any of the previous embodiments, whichis a chewable tablet.

24. Embodiment

A compressed tablet according to any of the previous embodiments,wherein the hardness of the tablet is between 70 to 250 or between 85 to250 N or between 70 to 200 N or between 85 to 200 N.

25. Embodiment

A tablet or a pharmaceutical composition according to any of theprevious embodiments, wherein the single oral dosage form containsbetween 800 mg to 3500 mg of sucroferric oxyhydroxide, or between 1500mg to 3500 mg of sucroferric oxyhydroxide, or between 1500 mg to 3000 mgof sucroferric oxyhydroxide.

26. Embodiment

A tablet or a pharmaceutical composition according to any of theprevious embodiments, wherein the single oral dosage form containsbetween 800 mg to 3500 mg of sucroferric oxyhydroxide, or between 1500mg to 3500 mg of sucroferric oxyhydroxide, or between 1500 mg to 3000 mgof sucroferric oxyhydroxide, and wherein at least 60%, or at least 80%,or at least 90% of the particles of the phosphate binder particle sizedistribution in the tablet are between 5 to 160 μm, and wherein the d50of the phosphate binder particle size distribution is between 40 μm to80 μm.

27. Embodiment

The use of particles comprising sucroferric oxyhydroxide for thepreparation of a compressed or a directly compressed tablet, wherein:

-   -   xx) at least 40%, or at least 60%, or at least 80%, or at least        90% of the sucroferric oxyhydroxide particles in the particle        size distribution are between 4 to 200 μm or preferably between        5 to 160 μm or between 21 to 160 μm, and/or    -   xxi) the sucroferric oxyhydroxide particles have a d50 in the        particle size distribution between 30 μm to 120 μm, or 35 μm to        110 μm, or 40 μm to 100 μm, or preferably between 40 μm to 80 μm        or in between 42 μm to 75 μm.

28. Embodiment

The use of sucroferric oxyhydroxide particles for the preparation of apharmaceutical composition or a compressed or a directly compressedtablet, wherein:

-   -   xxii) the sucroferric oxyhydroxide particles have a d50 in the        particle size distribution between 30 μm to 120 μm, or 35 μm to        110 μm, or 40 μm to 100 μm, or preferably between 40 μm to 80 μm        or in between 42 μm to 75 μm, and/or    -   xxiii) at least 40%, or at least 60%, or at least 80%, or at        least 90% of the sucroferric oxyhydroxide particles of the        particle size distribution are between 4 to 200 μm or preferably        between 5 to 160 μm or between 21 to 160 μm.

29. Embodiment

Use of the sucroferric oxyhydroxide particles according to embodiment 27or 28, wherein the sucroferric oxyhydroxide represents more than 80% ormore than 90%, or more than 95% of the sucroferric oxyhydroxideparticles, by weight on a dry weight basis of the pharmaceuticalcomposition or the compressed tablet.

30. Embodiment

A pharmaceutical formulation according to any of the previousembodiments, which is in the form of a powder or of granules which canfurther be mixed with at least one pharmaceutically acceptableexcipient.

31. Embodiment

A pharmaceutical formulation according to embodiment 30, in the form ofa powder to be directly compressed into a tablet or used forgranulation.

32. Embodiment

A pharmaceutical formulation, pharmaceutical composition, or acompressed tablet according to any of the previous embodiments, whichcomprises at least one further pharmaceutically acceptable excipient,selected from lubricants, preferably magnesium stearate.

33. Embodiment

Sucroferric oxyhydroxide particles comprising sucroferric oxyhydroxideand optionally at least one further pharmaceutically acceptableexcipient, wherein:

-   -   xxiv) at least 40%, or at least 60%, or at least 80%, or at        least 90% of the sucroferric oxyhydroxide particles in the        particle size distribution are between 4 to 200 μm or between 5        to 160 μm or between 21 to 160 μm,    -   xxv) the sucroferric oxyhydroxide particles have a d50 in the        particle size distribution of between 30 μm to 120 μm, or 35 μm        to 110 μm, or 40 μm to 100 μm, or preferably between 40 μm to 80        μm.

34. Embodiment

A tablet, a pharmaceutical formulation, a pharmaceutical composition ora use, according to any of the previous embodiments, wherein thesucroferric oxyhydroxide represents more than 80% or more than 90%, ormore than 95% of the sucroferric oxyhydroxide particles, by weight on adry weight basis of the particles.

35. Embodiment

Use of a pharmaceutical composition according to any of the previousembodiments, still in the form of a powder, for the manufacture acompressed tablet.

36. Embodiment

A tablet, a pharmaceutical composition or a use, according to any of theprevious embodiments, wherein at least 50%, or at least 60% of thesucroferric oxyhydroxide particles in the particle size distribution,have a particle size the range of 30 to 200 μm or preferably between 40to 200 μm.

37. Embodiment

A tablet, a pharmaceutical composition or a use according to any of theprevious embodiments, wherein the embodiment refers to a dry form of thetablet or of the pharmaceutical composition.

38. Embodiment

A tablet or a pharmaceutical composition according to any of theprevious embodiments, wherein the sucroferric oxyhydroxide particleshave a particle size distribution curve as depicted in FIG. 2.

39. Embodiment

A tablet or a pharmaceutical composition according to any of theprevious embodiments, wherein the sucroferric oxyhydroxide particleshave a particle size distribution curve in which the peak of the curveis between 50 μm and 90 μm.

The invention claimed is:
 1. A method of manufacturing a pharmaceuticalcomposition for oral administration, said method comprising: (i)combining sucroferric oxyhydroxide particles and at least onepharmaceutically acceptable excipient, wherein at least 80% by volume ofthe sucroferric oxyhydroxide particles have a particle size in the rangeof 4 μm to 200 μm and the d50 particle size distribution by volume ofthe sucroferric oxyhydroxide particles is in the range of 30 μm to 80μm; and (ii) tableting the combined sucroferric oxyhydroxide particlesand at least one pharmaceutically acceptable excipient from step (i) bycompression; wherein the pharmaceutical composition is in the form of achewable tablet; wherein the hardness of the chewable tablet is between100 N to 200 N as measured according to the European Pharmacopoeia01/2008:20908; wherein the weight of the chewable tablet is between 2000mg and 3000 mg; and wherein the chewable tablet has a disintegrationtime of between 5 minutes and 18 minutes as measured according to theEuropean Pharmacopoeia 04/2011:20901.
 2. The method according to claim1, wherein at least 80% by volume of the sucroferric oxyhydroxideparticles have a particle size in the range of 5 μm to 160 μm.
 3. Themethod according to claim 1, wherein at least 90% by volume of thesucroferric oxyhydroxide particles have a particle size in the range of4 μm to 200 μm.
 4. The method according to claim 1, wherein thefriability of the chewable tablet is between 0% to 7% as measuredaccording to the European Pharmacopoeia 01/2010:20907.
 5. The methodaccording to claim 1, wherein step (ii) is performed by directcompression.
 6. A method of manufacturing a pharmaceutical compositionfor oral administration, said method comprising: (i) combiningsucroferric oxyhydroxide particles and at least one pharmaceuticallyacceptable excipient, wherein the d50 particle size distribution byvolume of the sucroferric oxyhydroxide particles is in the range of 30μm to 80 μm; and (ii) tableting the combined sucroferric oxyhydroxideparticles and at least one pharmaceutically acceptable excipient fromstep (i) by compression; wherein the pharmaceutical composition is inthe form of a chewable tablet; wherein the pharmaceutical compositioncomprises about 2500 mg of sucroferric oxyhydroxide; wherein thehardness of the chewable tablet is between 100 N to 200 N as measuredaccording to the European Pharmacopoeia 01/2008:20908; and wherein thechewable tablet has a disintegration time of between 5 minutes and 18minutes as measured according to the European Pharmacopoeia04/2011:20901.
 7. The method according to claim 6, wherein at least 80%by volume of the sucroferric oxyhydroxide particles have a particle sizein the range of 4 μm to 200 μm.
 8. The method according to claim 6,wherein at least 80% by volume of the sucroferric oxyhydroxide particleshave a particle size in the range of 5 μm to 160 μm.
 9. The methodaccording to claim 6, wherein step (ii) is performed by directcompression.
 10. The method according to claim 6, wherein the friabilityof the chewable tablet is between 0% to 7% as measured according to theEuropean Pharmacopoeia 01/2010:20907.
 11. A method of manufacturing apharmaceutical composition for oral administration, said methodcomprising: (i) combining sucroferric oxyhydroxide particles and atleast one pharmaceutically acceptable excipient, wherein the d50particle size distribution by volume of said sucroferric oxyhydroxideparticles is in the range of 30 μm to 80 μm; and (ii) tableting thecombined sucroferric oxyhydroxide particles and at least onepharmaceutically acceptable excipient from step (i) by compression;wherein the pharmaceutical composition is in the form of a chewabletablet; wherein the weight of the chewable tablet is between 2000 mg and3000 mg; wherein the hardness of the chewable tablet is between 100 N to200 N as measured according to the European Pharmacopoeia 01/2008:20908;wherein the chewable tablet has a disintegration time of between 5minutes and 18 minutes as measured according to the EuropeanPharmacopoeia 04/2011:20901; and wherein more than 80% of the totalweight of the chewable tablet (by weight on a dry weight basis) issucroferric oxyhydroxide.
 12. The method according to claim 11, whereinat least 60% by volume of the sucroferric oxyhydroxide particles have aparticle size in the range of 4 μm to 200 μm.
 13. The method accordingto claim 11, wherein at least 80% by volume of the sucroferricoxyhydroxide particles have a particle size in the range of 4 μm to 200μm.
 14. The method according to claim 11, wherein at least 80% by volumeof the sucroferric oxyhydroxide particles have a particle size in therange of 5 μm to 160 μm.
 15. The method according to claim 11, whereinstep (ii) is performed by direct compression.
 16. The method accordingto claim 11, wherein the friability of the chewable tablet is between 0%to 7% as measured according to the European Pharmacopoeia 01/2010:20907.